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Stoffel CI, Eichhoff O, Cheng PF, Seiler L, Tellenbach F, Dzung A, Chiovaro F, Dummer R, Levesque MP. Protein Kinase C Inhibition Overcomes Targeted Therapy Resistance in Cutaneous Melanoma. Exp Dermatol 2025; 34:e70093. [PMID: 40243348 DOI: 10.1111/exd.70093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 03/14/2025] [Accepted: 03/19/2025] [Indexed: 04/18/2025]
Abstract
WNT5a expression is associated with a MAPK inhibitor resistant phenotype in melanoma driving cell polarity and invasion. No small molecules specifically targeting WNT5a are available. Promising results of targeting non-canonical WNT5a-dependent WNT signalling with a pan-PKC inhibitor in uveal melanoma prompted us to investigate the relevance of PKC inhibition in cutaneous melanoma. We revealed PKC signalling and WNT5a expression to be associated in a positive feedback loop, suggesting pan-PKC inhibitor as a potent inhibitor of WNT5a in cutaneous melanoma. Combinatorial PKC and MAPK pathway inhibition significantly reduced proliferation and invasion by induction of apoptosis in targeted therapy-resistant melanoma in vitro. In in vivo xenograft studies, we found less proliferation and apoptosis induction in the PKC inhibitor single and combination treatment group with MAPK pathway inhibitors than in the standard of care treatment group. Thus, targeting the non-canonical WNT signalling pathway via combinatorial PKC and MAPK pathway inhibition is beneficial for therapy-resistant cutaneous melanoma combating tumour heterogeneity in vivo. With our study, we are providing an alternate treatment strategy we think is worth investigating as future clinical interventions in cutaneous melanoma.
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Affiliation(s)
- Corinne I Stoffel
- Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Ossia Eichhoff
- Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Phil F Cheng
- Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Luzia Seiler
- Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Flavia Tellenbach
- Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Andreas Dzung
- Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | | | - Reinhard Dummer
- Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Mitchell P Levesque
- Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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2
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Crosignani S, Campos S, Bouix-Peter C, Harris C, Talbot E, Hu H, Wang S, Maclean J, Zanelli U, Taylor S, Foote K, Hacini-Rachinel F, Nicodeme E, Julia V. Discovery of a novel series of selective macrocyclic PKCTheta inhibitors. Bioorg Med Chem Lett 2024; 100:129630. [PMID: 38307441 DOI: 10.1016/j.bmcl.2024.129630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 01/20/2024] [Accepted: 01/27/2024] [Indexed: 02/04/2024]
Abstract
A series of macrocyclic PKCθ inhibitors based on a 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hinge binder has been studied. Different aromatic and heteroaromatic substituents have been explored in order to optimize potency, isoform selectivity as well as DMPK properties. The importance of the length of the macrocyclic linker has also been analyzed. In particular, it has been found that methyl substitutions on the linker can have a profound influence on both potency and metabolic stability. Several compounds showing very good profiles, suitable for in vivo testing, are disclosed.
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Affiliation(s)
| | - Sebastien Campos
- Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, UK
| | | | - Craig Harris
- Galderma SA, Av. d'Ouchy 4, 1006 Lausanne, Switzerland
| | - Eric Talbot
- Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, UK
| | - Haiyang Hu
- Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, UK
| | - Shun Wang
- Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, UK
| | - John Maclean
- Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, UK
| | - Ugo Zanelli
- Galderma SA, Av. d'Ouchy 4, 1006 Lausanne, Switzerland
| | - Simon Taylor
- Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, UK
| | - Kevin Foote
- Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, UK
| | | | | | - Valerie Julia
- Galderma SA, Av. d'Ouchy 4, 1006 Lausanne, Switzerland
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3
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Visser M, Papillon JPN, Luzzio M, LaMarche MJ, Fan J, Michael W, Wang D, Zhang A, Straub C, Mathieu S, Kato M, Palermo M, Chen C, Ramsey T, Joud C, Barrett R, Vattay A, Guo R, Bric A, Chung F, Liang G, Romanowski MJ, Lam J, Thohan S, Atassi F, Wylie A, Cooke VG. Discovery of Darovasertib (NVP-LXS196), a Pan-PKC Inhibitor for the Treatment of Metastatic Uveal Melanoma. J Med Chem 2024; 67:1447-1459. [PMID: 38198520 DOI: 10.1021/acs.jmedchem.3c02002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2024]
Abstract
Uveal melanoma (UM) is the most common primary intraocular malignancy in the adult eye. Despite the aggressive local management of primary UM, the development of metastases is common with no effective treatment options for metastatic disease. Genetic analysis of UM samples reveals the presence of mutually exclusive activating mutations in the Gq alpha subunits GNAQ and GNA11. One of the key downstream targets of the constitutively active Gq alpha subunits is the protein kinase C (PKC) signaling pathway. Herein, we describe the discovery of darovasertib (NVP-LXS196), a potent pan-PKC inhibitor with high whole kinome selectivity. The lead series was optimized for kinase and off target selectivity to afford a compound that is rapidly absorbed and well tolerated in preclinical species. LXS196 is being investigated in the clinic as a monotherapy and in combination with other agents for the treatment of uveal melanoma (UM), including primary UM and metastatic uveal melanoma (MUM).
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Affiliation(s)
- Michael Visser
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Julien P N Papillon
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Michael Luzzio
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Matthew J LaMarche
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Jianmei Fan
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Walter Michael
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - David Wang
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Alan Zhang
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Christopher Straub
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Simon Mathieu
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Mitsunori Kato
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Mark Palermo
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Christine Chen
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Timothy Ramsey
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Carol Joud
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Rosemary Barrett
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Anthony Vattay
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Ribo Guo
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Anka Bric
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Franklin Chung
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Guiqing Liang
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Michael J Romanowski
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Joni Lam
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Sanjeev Thohan
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Faraj Atassi
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Andrew Wylie
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Vesselina G Cooke
- Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
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Silnitsky S, Rubin SJS, Zerihun M, Qvit N. An Update on Protein Kinases as Therapeutic Targets-Part I: Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases. Int J Mol Sci 2023; 24:17600. [PMID: 38139428 PMCID: PMC10743896 DOI: 10.3390/ijms242417600] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Protein kinases are one of the most significant drug targets in the human proteome, historically harnessed for the treatment of cancer, cardiovascular disease, and a growing number of other conditions, including autoimmune and inflammatory processes. Since the approval of the first kinase inhibitors in the late 1990s and early 2000s, the field has grown exponentially, comprising 98 approved therapeutics to date, 37 of which were approved between 2016 and 2021. While many of these small-molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP binding pocket have been massively successful for oncological indications, their poor selectively for protein kinase isozymes have limited them due to toxicities in their application to other disease spaces. Thus, recent attention has turned to the use of alternative allosteric binding mechanisms and improved drug platforms such as modified peptides to design protein kinase modulators with enhanced selectivity and other pharmacological properties. Herein we review the role of different protein kinase C (PKC) isoforms in cancer and cardiovascular disease, with particular attention to PKC-family inhibitors. We discuss translational examples and carefully consider the advantages and limitations of each compound (Part I). We also discuss the recent advances in the field of protein kinase modulators, leverage molecular docking to model inhibitor-kinase interactions, and propose mechanisms of action that will aid in the design of next-generation protein kinase modulators (Part II).
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Affiliation(s)
- Shmuel Silnitsky
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel; (S.S.); (M.Z.)
| | - Samuel J. S. Rubin
- Department of Medicine, School of Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA;
| | - Mulate Zerihun
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel; (S.S.); (M.Z.)
| | - Nir Qvit
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel; (S.S.); (M.Z.)
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5
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Liu D, Li X, Zhang L, Hu B, Hu S, Zhang X, Hu J. Small molecule inhibitors of osteoarthritis: Current development and future perspective. Front Physiol 2023; 14:1156913. [PMID: 37089415 PMCID: PMC10119395 DOI: 10.3389/fphys.2023.1156913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 03/28/2023] [Indexed: 04/25/2023] Open
Abstract
Osteoarthritis (OA) is one of the common degenerative joint diseases in clinic. It mainly damages articular cartilage, causing pain, swelling and stiffness around joints, and is the main cause of disability of the elderly. Due to the unclear pathogenesis of osteoarthritis and the poor self-healing ability of articular cartilage, the treatment options for this disease are limited. At present, NSAIDs, Glucocorticoid and Duloxetine are the most commonly used treatment choice for osteoarthritis. Although it is somewhat effective, the adverse reactions are frequent and serious. The development of safer and more effective anti-osteoarthritis drugs is essential and urgent. This review summarizes recent advances in the pharmacological treatment of OA, focusing on small molecule inhibitors targeting cartilage remodeling in osteoarthritis as well as the research idea of reducing adverse effects by optimizing the dosage form of traditional drugs for the treatment of osteoarthritis. It should provide a reference for exploration of new potential treatment options.
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Affiliation(s)
- Dan Liu
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University (Third Military Medical University), Chongqing, China
| | - Xingxing Li
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University (Third Military Medical University), Chongqing, China
| | - Lin Zhang
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University (Third Military Medical University), Chongqing, China
| | - Bin Hu
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University (Third Military Medical University), Chongqing, China
| | - Sang Hu
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University (Third Military Medical University), Chongqing, China
| | - Xiao Zhang
- Institute of Pathology, The First Affiliated Hospital of Army Medical University (Third Military Medical University), Chongqing, China
- Chongqing Institute of Advanced Pathology, Jinfeng Laboratory, Chongqing, China
| | - Jing Hu
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University (Third Military Medical University), Chongqing, China
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6
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Kadagothy H, Nene S, Amulya E, Vambhurkar G, Rajalakshmi AN, Khatri DK, Singh SB, Srivastava S. Perspective insights of small molecules, phytoconstituents and biologics in the management of psoriasis: A focus on targeting major inflammatory cytokine pathways. Eur J Pharmacol 2023; 947:175668. [PMID: 36958476 DOI: 10.1016/j.ejphar.2023.175668] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 03/07/2023] [Accepted: 03/20/2023] [Indexed: 03/25/2023]
Abstract
Psoriasis is an enduring, pruritic and papulosquamous skin ailment that poses a significant burden on public health. It is mainly characterized by hyperkeratosis, acanthosis, parakeratosis, scaly and erythematous plaques. Biomarkers like interleukin-17, interleukin-12 and -23 and tumor necrosis factor-α serve as key drivers of psoriatic pathogenesis. Triggered release of pro-inflammatory cytokines from various up-regulated pathways leads to psoriatic inflammation. Several target moieties like biologics, small molecules and herbal moieties play a fundamental role in the repression of pathogenesis of psoriasis. Biologics and small molecules engaged in the management of psoriasis have been emphasized in detail. An insight into nano-carrier interventions on herbal moieties and clinical aspects of psoriasis are also highlighted. This review emphasizes various pathological targets involved in psoriasis.
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Affiliation(s)
- Husna Kadagothy
- Department of Pharmaceutics, Mother Theresa Post Graduate and Research Institute of Health Sciences, Puducherry, India
| | - Shweta Nene
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Etikala Amulya
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Ganesh Vambhurkar
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - A N Rajalakshmi
- Department of Pharmaceutics, Mother Theresa Post Graduate and Research Institute of Health Sciences, Puducherry, India
| | - Dharmendra Kumar Khatri
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Shashi Bala Singh
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Saurabh Srivastava
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India.
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7
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Autoreactive T-Cells in Psoriasis: Are They Spoiled Tregs and Can Therapies Restore Their Functions? Int J Mol Sci 2023; 24:ijms24054348. [PMID: 36901778 PMCID: PMC10002349 DOI: 10.3390/ijms24054348] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 02/10/2023] [Accepted: 02/13/2023] [Indexed: 02/25/2023] Open
Abstract
Psoriasis is a chronic inflammatory skin disease, which affects 2-4% of the population worldwide. T-cell derived factors such as Th17 and Th1 cytokines or cytokines such as IL-23, which favors Th17-expansion/differentiation, dominate in the disease. Therapies targeting these factors have been developed over the years. An autoimmune component is present, as autoreactive T-cells specific for keratins, the antimicrobial peptide LL37 and ADAMTSL5 have been described. Both autoreactive CD4 and CD8 T-cells exist, produce pathogenic cytokines, and correlate with disease activity. Along with the assumption that psoriasis is a T-cell-driven disease, Tregs have been studied extensively over the years, both in the skin and in circulation. This narrative review resumes the main findings about Tregs in psoriasis. We discuss how Tregs increase in psoriasis but are impaired in their regulatory/suppressive function. We debate the possibility that Tregs convert into T-effector cells under inflammatory conditions; for instance, they may turn into Th17-cells. We put particular emphasis on therapies that seem to counteract this conversion. We have enriched this review with an experimental section analyzing T-cells specific for the autoantigen LL37 in a healthy subject, suggesting that a shared specificity may exist between Tregs and autoreactive responder T-cells. This suggests that successful psoriasis treatments may, among other effects, restore Tregs numbers and functions.
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8
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Vorobjeva N, Dagil Y, Pashenkov M, Pinegin B, Chernyak B. Protein kinase C isoforms mediate the formation of neutrophil extracellular traps. Int Immunopharmacol 2023; 114:109448. [PMID: 36436472 DOI: 10.1016/j.intimp.2022.109448] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 11/02/2022] [Accepted: 11/09/2022] [Indexed: 11/27/2022]
Abstract
Neutrophils release extracellular traps (NETs) in response to numerous pathogenic microbes as the last suicidal resource (NETosis) in the fight against infection. Apart from the host defense function, NETs play an essential role in the pathogenesis of various autoimmune, inflammatory and malignant diseases. Therefore, understanding the molecular mechanisms of NETosis is important for regulating the aberrant or excessive NET release. Protein kinase C (PKC) is a serine/threonine kinase which is involved in various neutrophil functions, however, little is known about its implication in NETosis activated by various physiological and pharmacological stimuli. Since there are conventional, novel and atypical PKC isoforms (α, βI, βII, δ, and ζ) found in human neutrophils, we investigated their impact in NETosis, oxidative burst and spreading applying pharmacological approach. Using specific inhibitors of PKC isoforms, we showed that PKCβ, PKCδ, and PKCζ are involved in the oxidative burst, spreading and NETosis activated by calcium ionophore A23187, while only PKCβ is implicated in these functions activated by phorbol 12-myristate 13-acetate (PMA). The data obtained in our study might help in the development of new drugs useful for the treatment of autoimmune and inflammatory diseases associated with NETs.
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Affiliation(s)
- Nina Vorobjeva
- Dept. Immunology, Biology Faculty, Lomonosov Moscow State University, 119192 Moscow, Russia.
| | | | - Mikhail Pashenkov
- National Research Center Institute of Immunology of the Federal Medical-Biological Agency, Kashirskoe shosse 24, 115522 Moscow, Russia
| | - Boris Pinegin
- National Research Center Institute of Immunology of the Federal Medical-Biological Agency, Kashirskoe shosse 24, 115522 Moscow, Russia
| | - Boris Chernyak
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
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9
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Xu Z, Chu M. Advances in Immunosuppressive Agents Based on Signal Pathway. Front Pharmacol 2022; 13:917162. [PMID: 35694243 PMCID: PMC9178660 DOI: 10.3389/fphar.2022.917162] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 05/02/2022] [Indexed: 12/13/2022] Open
Abstract
Immune abnormality involves in various diseases, such as infection, allergic diseases, autoimmune diseases, as well as transplantation. Several signal pathways have been demonstrated to play a central role in the immune response, including JAK/STAT, NF-κB, PI3K/AKT-mTOR, MAPK, and Keap1/Nrf2/ARE pathway, in which multiple targets have been used to develop immunosuppressive agents. In recent years, varieties of immunosuppressive agents have been approved for clinical use, such as the JAK inhibitor tofacitinib and the mTOR inhibitor everolimus, which have shown good therapeutic effects. Additionally, many immunosuppressive agents are still in clinical trials or preclinical studies. In this review, we classified the immunosuppressive agents according to the immunopharmacological mechanisms, and summarized the phase of immunosuppressive agents.
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Affiliation(s)
- Zhiqing Xu
- Department of Immunology, National Health Commission (NHC) Key Laboratory of Medical Immunology (Peking University), School of Basic Medical Sciences, Peking University, Beijing, China
- Department of Pharmacology, Jilin University, Changchun, China
| | - Ming Chu
- Department of Immunology, National Health Commission (NHC) Key Laboratory of Medical Immunology (Peking University), School of Basic Medical Sciences, Peking University, Beijing, China
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10
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Gupta S, Shyamsundar K, Agrawal M, Vichare N, Biswas J. Current Knowledge of Biologics in Treatment of Noninfectious Uveitis. J Ocul Pharmacol Ther 2022; 38:203-222. [DOI: 10.1089/jop.2021.0098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Simple Gupta
- Department of Ophthalmology, Command Hospital, Pune, India
| | - K. Shyamsundar
- Department of Ophthalmology, Command Hospital, Pune, India
| | - Mohini Agrawal
- Department of Ophthalmology, Command Hospital, Pune, India
| | - Nitin Vichare
- Department of Ophthalmology, Command Hospital, Pune, India
| | - Jyotirmay Biswas
- Department of Uveitis and Ocular Pathology, Sankara Netralaya, Chennai, India
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11
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Sharma K, Choudhary S, Silakari O. Portraying molecular modulation and therapeutic aspects of psoriasis: Retrospection and current status. J Mol Struct 2021. [DOI: 10.1016/j.molstruc.2021.130770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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12
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Activators and Inhibitors of Protein Kinase C (PKC): Their Applications in Clinical Trials. Pharmaceutics 2021; 13:pharmaceutics13111748. [PMID: 34834162 PMCID: PMC8621927 DOI: 10.3390/pharmaceutics13111748] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/18/2021] [Accepted: 10/19/2021] [Indexed: 02/05/2023] Open
Abstract
Protein kinase C (PKC), a family of phospholipid-dependent serine/threonine kinase, is classed into three subfamilies based on their structural and activation characteristics: conventional or classic PKC isozymes (cPKCs; α, βI, βII, and γ), novel or non-classic PKC isozymes (nPKCs; δ, ε, η, and θ), and atypical PKC isozymes (aPKCs; ζ, ι, and λ). PKC inhibitors and activators are used to understand PKC-mediated intracellular signaling pathways and for the diagnosis and treatment of various PKC-associated diseases, such as cancers, neurological diseases, cardiovascular diseases, and infections. Many clinical trials of PKC inhibitors in cancers showed no significant clinical benefits, meaning that there is a limitation to design a cancer therapeutic strategy targeting PKC alone. This review will focus on the activators and inhibitors of PKC and their applications in clinical trials.
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13
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Papa P, Whitefield B, Mortensen DS, Cashion D, Huang D, Torres E, Parnes J, Sapienza J, Hansen J, Correa M, Delgado M, Harris R, Hegde S, Norris S, Bahmanyar S, Plantevin-Krenitsky V, Liu Z, Leftheris K, Kulkarni A, Bennett B, Hur EM, Ringheim G, Khambatta G, Chan H, Muir J, Blease K, Burnett K, LeBrun L, Morrison L, Celeridad M, Khattri R, Cathers BE. Discovery of the Selective Protein Kinase C-θ Kinase Inhibitor, CC-90005. J Med Chem 2021; 64:11886-11903. [PMID: 34355886 DOI: 10.1021/acs.jmedchem.1c00388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead (3) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 (57) was selected for clinical development.
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Affiliation(s)
- Patrick Papa
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Brandon Whitefield
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Deborah S Mortensen
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Dan Cashion
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Dehua Huang
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Eduardo Torres
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Jason Parnes
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - John Sapienza
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Joshua Hansen
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Matthew Correa
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Mercedes Delgado
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Roy Harris
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Sayee Hegde
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Stephen Norris
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Sogole Bahmanyar
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | | | - Zheng Liu
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Katerina Leftheris
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Ashutosh Kulkarni
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Brydon Bennett
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Eun Mi Hur
- Bristol Myers Squibb, 86 Morris Avenue, Summit, New Jersey 07901, United States
| | - Garth Ringheim
- Bristol Myers Squibb, 86 Morris Avenue, Summit, New Jersey 07901, United States
| | - Godrej Khambatta
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Henry Chan
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Jeffrey Muir
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Kate Blease
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Kelven Burnett
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Laurie LeBrun
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Lisa Morrison
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Maria Celeridad
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Roli Khattri
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Brian E Cathers
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
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14
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Parlakpinar H, Gunata M. Transplantation and immunosuppression: a review of novel transplant-related immunosuppressant drugs. Immunopharmacol Immunotoxicol 2021; 43:651-665. [PMID: 34415233 DOI: 10.1080/08923973.2021.1966033] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Immunosuppressive drugs used in the transplantation period are generally defined as induction and maintenance therapy. The use of immunosuppressants, which are particularly useful and have fewer side effects, decreased both mortality and morbidity. Many drugs such as steroids, calcineurin inhibitors (cyclosporine-A, tacrolimus), antimetabolites (mycophenolate mofetil, azathioprine), and mTOR inhibitors (sirolimus, everolimus) are used as immunosuppressive agents. Although immunosuppressant drugs cause many side effects such as hypertension, infection, and hyperlipidemia, they are the agents that should be used to prevent organ rejection. This shows the importance of individualized drug use. The optimal immunosuppressive therapy post-transplant is not established. Therefore, discovering less toxic but more potent new agents is of great importance, and new experimental and clinical studies are needed in this regard.Our review discussed the mechanism of immunosuppressants, new agents' discovery, and current therapeutic protocols in the transplantation.
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Affiliation(s)
- Hakan Parlakpinar
- Department of Medical Pharmacology, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Mehmet Gunata
- Department of Medical Pharmacology, Faculty of Medicine, Inonu University, Malatya, Turkey
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15
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Singh RK, Kumar S, Tomar MS, Verma PK, Kumar A, Kumar S, Kumar N, Singh JP, Acharya A. Putative role of natural products as Protein Kinase C modulator in different disease conditions. ACTA ACUST UNITED AC 2021; 29:397-414. [PMID: 34216003 DOI: 10.1007/s40199-021-00401-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 05/25/2021] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Protein kinase C (PKC) is a promising drug target for various therapeutic areas. Natural products derived from plants, animals, microorganisms, and marine organisms have been used by humans as medicine from prehistoric times. Recently, several compounds derived from plants have been found to modulate PKC activities through competitive binding with ATP binding site, and other allosteric regions of PKC. As a result fresh race has been started in academia and pharmaceutical companies to develop an effective naturally derived small-molecule inhibitor to target PKC activities. Herein, in this review, we have discussed several natural products and their derivatives, which are reported to have an impact on PKC signaling cascade. METHODS All information presented in this review article regarding the regulation of PKC by natural products has been acquired by a systematic search of various electronic databases, including ScienceDirect, Scopus, Google Scholar, Web of science, ResearchGate, and PubMed. The keywords PKC, natural products, curcumin, rottlerin, quercetin, ellagic acid, epigallocatechin-3 gallate, ingenol 3 angelate, resveratrol, protocatechuic acid, tannic acid, PKC modulators from marine organism, bryostatin, staurosporine, midostaurin, sangivamycin, and other relevant key words were explored. RESULTS The natural products and their derivatives including curcumin, rottlerin, quercetin, ellagic acid, epigallocatechin-3 gallate, ingenol 3 angelate, resveratrol, bryostatin, staurosporine, and midostaurin play a major role in the management of PKC activity during various disease progression. CONCLUSION Based on the comprehensive literature survey, it could be concluded that various natural products can regulate PKC activity during disease progression. However, extensive research is needed to circumvent the challenge of isoform specific regulation of PKC by natural products.
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Affiliation(s)
- Rishi Kant Singh
- Department of Zoology, Institute of Science, BHU, Varanasi, 221005, India
| | | | - Munendra Singh Tomar
- Department of Pharmaceutical Science, School of Pharmacy, University of Colorado, Denver, USA
| | | | - Amit Kumar
- Department of Zoology, Institute of Science, BHU, Varanasi, 221005, India
| | - Sandeep Kumar
- Department of Zoology, Institute of Science, BHU, Varanasi, 221005, India
| | - Naveen Kumar
- Department of Zoology, Institute of Science, BHU, Varanasi, 221005, India
| | - Jai Prakash Singh
- Department of Panchkarma, Institute of Medical Science, BHU, Varanasi, India, 221005
| | - Arbind Acharya
- Department of Zoology, Institute of Science, BHU, Varanasi, 221005, India.
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16
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Ziegler R, Häusermann F, Kirchner S, Polonchuk L. Cardiac Safety of Kinase Inhibitors - Improving Understanding and Prediction of Liabilities in Drug Discovery Using Human Stem Cell-Derived Models. Front Cardiovasc Med 2021; 8:639824. [PMID: 34222360 PMCID: PMC8242589 DOI: 10.3389/fcvm.2021.639824] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 03/31/2021] [Indexed: 11/13/2022] Open
Abstract
Many small molecule kinase inhibitors (SMKIs) used to fight cancer have been associated with cardiotoxicity in the clinic. Therefore, preventing their failure in clinical development is a priority for preclinical discovery. Our study focused on the integration and concurrent measurement of ATP, apoptosis dynamics and functional cardiac indexes in human stem cell-derived cardiomyocytes (hSC-CMs) to provide further insights into molecular determinants of compromised cardiac function. Ten out of the fourteen tested SMKIs resulted in a biologically relevant decrease in either beating rate or base impedance (cell number index), illustrating cardiotoxicity as one of the major safety liabilities of SMKIs, in particular of those involved in the PI3K–AKT pathway. Pearson's correlation analysis indicated a good correlation between the different read-outs of functional importance. Therefore, measurement of ATP concentrations and apoptosis in vitro could provide important insight into mechanisms of cardiotoxicity. Detailed investigation of the cellular signals facilitated multi-parameter evaluation allowing integrative assessment of cardiomyocyte behavior. The resulting correlation can be used as a tool to highlight changes in cardiac function and potentially to categorize drugs based on their mechanisms of action.
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Affiliation(s)
- Ricarda Ziegler
- Pharmaceutical Sciences, Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - Fabian Häusermann
- Pharmaceutical Sciences, Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - Stephan Kirchner
- Pharmaceutical Sciences, Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - Liudmila Polonchuk
- Pharmaceutical Sciences, Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
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17
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Parker PJ, Brown SJ, Calleja V, Chakravarty P, Cobbaut M, Linch M, Marshall JJT, Martini S, McDonald NQ, Soliman T, Watson L. Equivocal, explicit and emergent actions of PKC isoforms in cancer. Nat Rev Cancer 2021; 21:51-63. [PMID: 33177705 DOI: 10.1038/s41568-020-00310-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/02/2020] [Indexed: 01/02/2023]
Abstract
The maturing mutational landscape of cancer genomes, the development and application of clinical interventions and evolving insights into tumour-associated functions reveal unexpected features of the protein kinase C (PKC) family of serine/threonine protein kinases. These advances include recent work showing gain or loss-of-function mutations relating to driver or bystander roles, how conformational constraints and plasticity impact this class of proteins and how emergent cancer-associated properties may offer opportunities for intervention. The profound impact of the tumour microenvironment, reflected in the efficacy of immune checkpoint interventions, further prompts to incorporate PKC family actions and interventions in this ecosystem, informed by insights into the control of stromal and immune cell functions. Drugging PKC isoforms has offered much promise, but when and how is not obvious.
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Affiliation(s)
- Peter J Parker
- Protein Phosphorylation Laboratory, Francis Crick Institute, London, UK.
- School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Campus, London, UK.
| | - Sophie J Brown
- Protein Phosphorylation Laboratory, Francis Crick Institute, London, UK
| | - Veronique Calleja
- Protein Phosphorylation Laboratory, Francis Crick Institute, London, UK
| | | | - Mathias Cobbaut
- Protein Phosphorylation Laboratory, Francis Crick Institute, London, UK
| | - Mark Linch
- UCL Cancer Institute, University College London, London, UK
| | | | - Silvia Martini
- Protein Phosphorylation Laboratory, Francis Crick Institute, London, UK
| | - Neil Q McDonald
- Signalling and Structural Biology Laboratory, Francis Crick Institute, London, UK
- Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, London, UK
| | - Tanya Soliman
- Centre for Cancer Genomics and Computational Biology, Bart's Cancer Institute, London, UK
| | - Lisa Watson
- Protein Phosphorylation Laboratory, Francis Crick Institute, London, UK
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18
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Pang C, Wen L, Qin H, Zhu B, Lu X, Luo S. Sotrastaurin, a PKC inhibitor, attenuates RANKL-induced bone resorption and attenuates osteochondral pathologies associated with the development of OA. J Cell Mol Med 2020; 24:8452-8465. [PMID: 32652826 PMCID: PMC7412701 DOI: 10.1111/jcmm.15404] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 04/29/2020] [Accepted: 05/03/2020] [Indexed: 12/19/2022] Open
Abstract
Osteoarthritis (OA) is a common degenerative disease that affects the musculoskeletal structure of the whole joint, which is characterized by progressive destruction of both articular cartilage and subchondral bone. Treatment of the bone pathologies, particularly osteoclast‐mediated subchondral bone loss in the early stages of OA, could prevent subsequent cartilage degeneration and progression of OA. In the present study, the PKC inhibitor, Sotrastaurin, was found to inhibit RANKL‐induced osteoclast formation in vitro in a dose‐ and time‐dependent manner. In particular, SO exerted its anti‐osteoclastic effect predominantly at the early stages of RANKL stimulation, suggesting inhibitory effects on precursor cell fusion. Using mature osteoclasts cultured on bovine bone discs, we showed that SO also exerts anti‐resorptive effects on mature osteoclasts bone resorptive function. Mechanistically, SO attenuates the early activation of the p38, ERK and JNK signalling pathways, leeding to impaired induction of crucial osteoclast transcription factors c‐Jun, c‐Fos and NFATc1. We also showed that SO treatment significantly inhibited the phosphorylation of PKCδ and MARCKS, an upstream regulator of cathepsin K secretion. Finally, in animal studies, SO significantly alleviates the osteochondral pathologies of subchondral bone destruction as well as articular cartilage degeneration following DMM‐induced OA, markedly improving OARSI scores. The reduced subchondral bone loss was associated with marked reductions in TRAP(+) osteoclasts in the subchondral bone tissue. Collectively, our data provide evidence for the protective effects of SO against OA by preventing aberrant subchondral bone and articular cartilage changes. Thus, SO demonstrates potential for further development as an alternative therapeutic option against OA.
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Affiliation(s)
- Cong Pang
- Department of Orthopedics, The Ninth Affiliated Hospital of Guangxi Medical University, Beihai, China.,Department of Orthopedics, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Liangbao Wen
- Department of Neurosurgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Haikuo Qin
- Department of Orthopedics, The Ninth Affiliated Hospital of Guangxi Medical University, Beihai, China
| | - Bikang Zhu
- Department of Orthopedics, The Ninth Affiliated Hospital of Guangxi Medical University, Beihai, China
| | - Xuanyuan Lu
- Department of Orthopedics, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Shixing Luo
- Department of Orthopedics, The Ninth Affiliated Hospital of Guangxi Medical University, Beihai, China
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19
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Sernicola A, Russo I, Alaibac M. Small-molecule-based immunotherapy for immunologically mediated skin conditions. Immunotherapy 2020; 12:417-429. [PMID: 32308089 DOI: 10.2217/imt-2019-0190] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
A better understanding of the molecular pathogenesis of cutaneous immune disorders, together with advances in pharmaceutical drug development, led to the introduction of small-molecule inhibitors in the therapeutic management of a large spectrum of skin immune conditions. Small molecules are agents with a low molecular weight that are capable of affecting proinflammatory pathways through modulation of intracellular targets. These agents promise to improve the therapeutic management of many skin immune disorders due to their easy administration, high bioavailability and favorable safety profile. Here, we review the major small-molecule inhibitors targeting receptor-associated kinases, second messengers and transcription factors in development for the treatment of cutaneous immune conditions.
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Affiliation(s)
- Alvise Sernicola
- Unit of Dermatology, University of Padua, Via Gallucci 4, 35128 Padova, Italy
| | - Irene Russo
- Unit of Dermatology, University of Padua, Via Gallucci 4, 35128 Padova, Italy
| | - Mauro Alaibac
- Unit of Dermatology, University of Padua, Via Gallucci 4, 35128 Padova, Italy
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20
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Collier PN, Twin HC, Knegtel RMA, Boyall D, Brenchley G, Davis CJ, Keily S, Mak C, Miller A, Pierard F, Settimo L, Bolton CM, Chiu P, Curnock A, Doyle E, Tanner AJ, Jimenez JM. Discovery of Selective, Orally Bioavailable Pyrazolopyridine Inhibitors of Protein Kinase Cθ (PKCθ) That Ameliorate Symptoms of Experimental Autoimmune Encephalomyelitis. ACS Med Chem Lett 2019; 10:1134-1139. [PMID: 31417666 DOI: 10.1021/acsmedchemlett.9b00134] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 06/27/2019] [Indexed: 11/28/2022] Open
Abstract
PKCθ plays an important role in T cell biology and is a validated target for a number of disease states. A series of potent and selective PKCθ inhibitors were designed and synthesized starting from a HTS hit compound. Cell activity, while initially a challenge to achieve, was built into the series by transforming the nitrile unit of the scaffold into a primary amine, the latter predicted to form a new hydrogen bond to Asp508 near the entrance of the ATP binding site of PKCθ. Significant improvements in physiochemical parameters were observed on introduction of an oxetane group proximal to a primary amine leading to compound 22, which demonstrated a reduction of symptoms in a mouse model of multiple sclerosis.
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Affiliation(s)
- Philip N. Collier
- Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Elisabeth Doyle
- Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States
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21
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Slivka PF, Hsieh CL, Lipovsky A, Pratt SD, Locklear J, Namovic MT, McDonald HA, Wetter J, Edelmayer R, Hu M, Murphy E, Domanus M, Lu C, Duggan R, King J, Scott VE, Donnelly-Roberts D, Slavin A, Gopalakrishnan S, Chung N, Goedken ER. Small Molecule and Pooled CRISPR Screens Investigating IL17 Signaling Identify BRD2 as a Novel Contributor to Keratinocyte Inflammatory Responses. ACS Chem Biol 2019; 14:857-872. [PMID: 30938974 DOI: 10.1021/acschembio.8b00260] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Interleukin-17A (IL17A) plays a critical role in the development of numerous autoimmune diseases, including psoriasis. The clinical success of IL17A neutralizing biologics in psoriasis has underlined its importance as a drug discovery target. While many studies have focused on the differentiation and trafficking of IL17A producing T-helper 17 cells, less is known about IL17A-initiated signaling events in stromal and parenchymal cells leading to psoriatic phenotypes. We sought to discover signaling nodes downstream of IL17A contributing to disease pathogenesis. Using IL17A and tumor necrosis factor α (TNF) to stimulate primary human epidermal keratinocytes, we employed two different phenotypic screening approaches. First, a library of ∼22000 annotated compounds was screened for reduced secretion of the pro-inflammatory chemokine IL8. Second, a library of 729 kinases was screened in a pooled format by utilizing CRISPR-Cas9 and monitoring IL8 intracellular staining. The highest-ranking novel hits identified in both screens were the bromodomain and extra-terminal domain (BET) family proteins and bromodomain-containing protein 2 (BRD2), respectively. Comparison of BRD2, BRD3, and BRD4 silencing with siRNA and CRISPR confirmed that BRD2 was responsible for mediating IL8 production. Pan-BRD inhibitors and BRD2 knockout also reduced IL17A/TNF-mediated CXC motif chemokines 1/2/6 (CXCL1/2/6) and granulocyte colony stimulating factor (G-CSF) production. In RNA-Seq analysis, 438 IL17A/TNF dependent genes were reduced in BRD2-deficient primary keratinocytes. KEGG pathway analysis of these genes showed enrichment in TNF signaling and rheumatoid arthritis relevant genes. Moreover, a number of genes important for keratinocyte homeostasis and cornification were dysregulated in BRD2-deficient keratinocytes. In IL17A/TNF/IL22 stimulated three-dimensional organotypic raft cultures, pan-BRD inhibition reduced inflammatory factor production but elicited aberrant cornification, consistent with RNA-Seq analysis. These studies highlight a novel role for BRDs and BRD2 in particular in IL17A-mediated inflammatory signaling.
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Affiliation(s)
- Peter F. Slivka
- Discovery Dermatology & Fibrosis, AbbVie Bioresearch Center, Worcester, Massachusetts 01605, United States
| | - Chen-Lin Hsieh
- Genomics Research Center, AbbVie Inc., North Chicago, Illinois 60064, United States
| | - Alex Lipovsky
- Discovery Dermatology & Fibrosis, AbbVie Bioresearch Center, Worcester, Massachusetts 01605, United States
| | - Steven D. Pratt
- Target Enabling Science & Technology, AbbVie Inc., North Chicago, Illinois 60064, United States
| | - John Locklear
- Target Enabling Science & Technology, AbbVie Inc., North Chicago, Illinois 60064, United States
- PerkinElmer Life Sciences, Waltham, Massachusetts 02451, United States
| | - Marian T. Namovic
- Target Enabling Science & Technology, AbbVie Inc., North Chicago, Illinois 60064, United States
| | - Heath A. McDonald
- Discovery Dermatology & Fibrosis, AbbVie Inc., North Chicago, Illinois 60064, United States
| | - Joseph Wetter
- Discovery Dermatology & Fibrosis, AbbVie Inc., North Chicago, Illinois 60064, United States
| | - Rebecca Edelmayer
- Discovery Dermatology & Fibrosis, AbbVie Inc., North Chicago, Illinois 60064, United States
| | - Min Hu
- Genomics Research Center, AbbVie Inc., North Chicago, Illinois 60064, United States
| | - Erin Murphy
- Genomics Research Center, AbbVie Inc., North Chicago, Illinois 60064, United States
| | - Marc Domanus
- Genomics Research Center, AbbVie Inc., North Chicago, Illinois 60064, United States
| | - Charles Lu
- Genomics Research Center, AbbVie Inc., North Chicago, Illinois 60064, United States
| | - Ryan Duggan
- Immuno-Oncology Discovery, AbbVie Inc., North Chicago, Illinois 60064, United States
| | - Jacob King
- Discovery Dermatology & Fibrosis, AbbVie Bioresearch Center, Worcester, Massachusetts 01605, United States
| | - Victoria E. Scott
- Discovery Dermatology & Fibrosis, AbbVie Inc., North Chicago, Illinois 60064, United States
| | - Diana Donnelly-Roberts
- Target Enabling Science & Technology, AbbVie Inc., North Chicago, Illinois 60064, United States
| | - Anthony Slavin
- Immunology Pharmacology, AbbVie Bioresearch Center, Worcester, Massachusetts 01605, United States
| | - Sujatha Gopalakrishnan
- Target Enabling Science & Technology, AbbVie Inc., North Chicago, Illinois 60064, United States
| | - Namjin Chung
- Genomics Research Center, AbbVie Inc., North Chicago, Illinois 60064, United States
| | - Eric R. Goedken
- Discovery Dermatology & Fibrosis, AbbVie Bioresearch Center, Worcester, Massachusetts 01605, United States
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22
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Madden SK, Flanagan KL, Jones G. How lifestyle factors and their associated pathogenetic mechanisms impact psoriasis. Clin Nutr 2019; 39:1026-1040. [PMID: 31155371 DOI: 10.1016/j.clnu.2019.05.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 04/11/2019] [Accepted: 05/06/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUNDS AND AIMS Psoriasis is a skin disorder affecting approximately 2-3% of the global population. While research has revealed a strong genetic component, there are few studies exploring the extent to which lifestyle factors influence psoriasis pathogenesis. The aim of this review was to describe the role of lifestyle factors as both a potential cause and treatment for psoriasis. The review also examines the underlying mechanisms through which these lifestyle factors may operate. METHODS This narrative review aims to incorporate current knowledge relating to both lifestyle and pathogenetic factors that contribute to and alleviate psoriasis presentation. Studies reporting the effect of an inflammatory diet and potential dietary benefits are reported, as well as insights into the effects of stress, smoking and alcohol, insulin resistance and exercise. RESULTS Poor nutrition and low Omega 3 fatty acid intake, likely combined with fat malabsorption caused by gut dysbiosis and systemic inflammation, are associated with psoriasis. The data strongly suggest that improvements to disease severity can be made through dietary and lifestyle interventions and increased physical activity. Less conclusive, although worthy of mention, is the beneficial effect of bile acid supplementation. CONCLUSIONS Lifestyle interventions are a promising treatment for psoriasis and its associated co-morbidities. However, gaps and inadequacies exist within the literature, e.g. methodology, absence of a unified scoring system, lack of controlled clinical data and lack of studies without simultaneous usage of biologics or alternative therapies. Future directions should focus on high quality cohort studies and clinical trials.
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Affiliation(s)
- Seonad K Madden
- School of Health Sciences, College of Health and Medicine, University of Tasmania, Australia.
| | - Katie L Flanagan
- School of Medicine, College of Health and Medicine, University of Tasmania, Australia; School of Health & Biomedical Science, Royal Melbourne Institute of Technology, Australia; Infectious Diseases Service, Launceston General Hospital, Australia; Dept. of Immunology and Pathology, Monash University, Australia
| | - Graeme Jones
- Menzies Institute for Medical Research, University of Tasmania, Australia
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23
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Bell M, Foley D, Naylor C, Robinson C, Riley J, Epemolu O, Scullion P, Shishikura Y, Katz E, McLean WHI, Wyatt P, Read KD, Woodland A. Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1. Bioorg Med Chem Lett 2018; 28:3255-3259. [PMID: 30143424 PMCID: PMC6185871 DOI: 10.1016/j.bmcl.2018.07.044] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 07/19/2018] [Accepted: 07/29/2018] [Indexed: 11/11/2022]
Abstract
The oral S1PR1 agonist ponesimod demonstrated substantial efficacy in a phase II clinical trial of psoriasis. Unfortunately, systemic side effects were observed, which included lymphopenia and transient bradycardia. We sought to develop a topical soft-drug S1PR1 agonist with an improved therapeutic index. By modifying ponesimod, we discovered an ester series of S1PR agonists. To increase metabolic instability in plasma we synthesised esters described as specific substrates for paraoxonase and butyrylcholinesterases, esterases present in human plasma.
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Affiliation(s)
- Mark Bell
- The Drug Discovery Unit, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 4HN, UK.
| | - David Foley
- The Drug Discovery Unit, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 4HN, UK
| | - Claire Naylor
- The Drug Discovery Unit, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 4HN, UK
| | - Colin Robinson
- The Drug Discovery Unit, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 4HN, UK
| | - Jennifer Riley
- The Drug Discovery Unit, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 4HN, UK
| | - Ola Epemolu
- The Drug Discovery Unit, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 4HN, UK
| | - Paul Scullion
- The Drug Discovery Unit, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 4HN, UK
| | - Yoko Shishikura
- The Drug Discovery Unit, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 4HN, UK
| | - Elad Katz
- The Drug Discovery Unit, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 4HN, UK
| | - W H Irwin McLean
- Dermatology and Genetic Medicine, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK
| | - Paul Wyatt
- The Drug Discovery Unit, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 4HN, UK
| | - Kevin D Read
- The Drug Discovery Unit, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 4HN, UK
| | - Andrew Woodland
- The Drug Discovery Unit, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 4HN, UK.
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24
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Golant AK, Guttman-Yassky E. Psoriasis Treatments: A Review of the Current Research Pipeline. ACTA ACUST UNITED AC 2018. [DOI: 10.1177/247553031117a00102] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Psoriasis treatment is aimed at suppressing skin lesions and preventing relapses. Although in the last decade biological therapies have revolutionized the pharmacologic treatment armamentarium for psoriasis, many patients are still inadequately controlled with currently available therapeutics. An advanced understanding of the immunopathogensis of psoriasis has led to development of new drugs that refine existing treatments or target novel molecular and immunologic pathways. Here we review the most promising topical, oral, and injectable psoriasis treatments in the research pipeline, including agents that target cytokines interleukin (IL)-12/23, tumor necrosis factor-α, IL-20, IL-17, IL-22, inhibitors of calcineurin, phosphodiesterase type 4, protein kinase C, Janus kinase, p38 kinase, purine nucleotide phosphorylase, adenosine receptor agonists, and recombinant chaperonin protein. These targeted therapeutics offer the potential for greater clinical efficacy and less toxicity than traditional agents. As the number of treatment options continues to expand, clinicians will have more diverse opportunities to help patients achieve better psoriasis control.
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Affiliation(s)
| | - Emma Guttman-Yassky
- Department of Dermatology, Weill Cornell Medical Center, Cornell University, New York
- Laboratory for Investigative Dermatology, New York, New York
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Bailey LJ, Choudhary V, Bollag WB. Possible Role of Phosphatidylglycerol-Activated Protein Kinase C-βII in Keratinocyte Differentiation. ACTA ACUST UNITED AC 2017; 11:59-71. [PMID: 32528559 PMCID: PMC7289045 DOI: 10.2174/1874372201711010059] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Background The epidermis is a continuously regenerating tissue maintained by a balance between proliferation and differentiation, with imbalances resulting in skin disease. We have previously found that in mouse keratinocytes, the lipid-metabolizing enzyme phospholipase D2 (PLD2) is associated with the aquaglyceroporin, aquaporin 3 (AQP3), an efficient transporter of glycerol. Our results also show that the functional interaction of AQP3 and PLD2 results in increased levels of phosphatidylglycerol (PG) in response to an elevated extracellular calcium level, which triggers keratinocyte differentiation. Indeed, we showed that directly applying PG can promote keratinocyte differentiation. Objective We hypothesized that the differentiative effects of this PLD2/AQP3/PG signaling cascade, in which AQP3 mediates the transport of glycerol into keratinocytes followed by its PLD2-catalyzed conversion to PG, are mediated by protein kinase CβII (PKCβII), which contains a PG-binding domain in its carboxy-terminus. Method: To test this hypothesis we used quantitative RT-PCR, western blotting and immunocytochemistry. Results We first verified the presence of PKCβII mRNA and protein in mouse keratinocytes. Next, we found that autophosphorylated (activated) PKCβII was redistributed upon treatment of keratinocytes with PG. In the unstimulated state phosphoPKCβII was found in the cytosol and perinuclear area; treatment with PG resulted in enhanced phosphoPKCβII localization in the perinuclear area. PG also induced translocation of phosphoPKCβII to the plasma membrane. In addition, we observed that overexpression of PKCβII enhanced calcium- and PG-induced keratinocyte differentiation without affecting calcium-inhibited keratinocyte proliferation. Conclusion These results suggest that the PG produced by the PLD2/AQP3 signaling module may function by activating PKCβII.
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Affiliation(s)
- Lakiea J Bailey
- Department of Physiology, 1120 15th Street, Medical College of Georgia at Augusta University (formerly Georgia Regents University), Augusta, GA 30912, USA
| | - Vivek Choudhary
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA.,Department of Physiology, 1120 15th Street, Medical College of Georgia at Augusta University (formerly Georgia Regents University), Augusta, GA 30912, USA
| | - Wendy B Bollag
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA.,Department of Physiology, 1120 15th Street, Medical College of Georgia at Augusta University (formerly Georgia Regents University), Augusta, GA 30912, USA
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He X, Koenen HJ, Slaats JH, Joosten I. Stabilizing human regulatory T cells for tolerance inducing immunotherapy. Immunotherapy 2017; 9:735-751. [PMID: 28771099 DOI: 10.2217/imt-2017-0017] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Many autoimmune diseases develop as a consequence of an altered balance between autoreactive immune cells and suppressive FOXP3+ Treg. Restoring this balance through amplification of Treg represents a promising strategy to treat disease. However, FOXP3+ Treg might become unstable especially under certain inflammatory conditions, and might transform into proinflammatory cytokine-producing cells. The issue of heterogeneity and instability of Treg has caused considerable debate in the field and has important implications for Treg-based immunotherapy. In this review, we discuss how Treg stability is defined and what the molecular mechanisms underlying the maintenance of FOXP3 expression and the regulation of Treg stability are. Also, we elaborate on current strategies used to stabilize human Treg for clinical purposes. This review focuses on human Treg, but considering that cell-intrinsic mechanisms to regulate Treg stability in mice and in humans might be similar, data derived from mice studies are also discussed in this paper.
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Affiliation(s)
- Xuehui He
- Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.,College of Computer Science, Qinghai Normal University, Xining, Qinghai, China
| | - Hans Jpm Koenen
- Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jeroen Hr Slaats
- Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Irma Joosten
- Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
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Isakov N. Protein kinase C (PKC) isoforms in cancer, tumor promotion and tumor suppression. Semin Cancer Biol 2017; 48:36-52. [PMID: 28571764 DOI: 10.1016/j.semcancer.2017.04.012] [Citation(s) in RCA: 173] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 03/22/2017] [Accepted: 04/25/2017] [Indexed: 12/27/2022]
Abstract
The AGC family of serine/threonine kinases (PKA, PKG, PKC) includes more than 60 members that are critical regulators of numerous cellular functions, including cell cycle and differentiation, morphogenesis, and cell survival and death. Mutation and/or dysregulation of AGC kinases can lead to malignant cell transformation and contribute to the pathogenesis of many human diseases. Members of one subgroup of AGC kinases, the protein kinase C (PKC), have been singled out as critical players in carcinogenesis, following their identification as the intracellular receptors of phorbol esters, which exhibit tumor-promoting activities. This observation attracted the attention of researchers worldwide and led to intense investigations on the role of PKC in cell transformation and the potential use of PKC as therapeutic drug targets in cancer diseases. Studies demonstrated that many cancers had altered expression and/or mutation of specific PKC genes. However, the causal relationships between the changes in PKC gene expression and/or mutation and the direct cause of cancer remain elusive. Independent studies in normal cells demonstrated that activation of PKC is essential for the induction of cell activation and proliferation, differentiation, motility, and survival. Based on these observations and the general assumption that PKC isoforms play a positive role in cell transformation and/or cancer progression, many PKC inhibitors have entered clinical trials but the numerous attempts to target PKC in cancer has so far yielded only very limited success. More recent studies demonstrated that PKC function as tumor suppressors, and suggested that future clinical efforts should focus on restoring, rather than inhibiting, PKC activity. The present manuscript provides some historical perspectives on the tumor promoting function of PKC, reviewing some of the observations linking PKC to cancer progression, and discusses the role of PKC in the pathogenesis of cancer diseases and its potential usage as a therapeutic target.
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Affiliation(s)
- Noah Isakov
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences and the Cancer Research Center, Ben Gurion University of the Negev, P.O.B. 653, Beer Sheva 84105, Israel.
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Protein Kinases C-Mediated Regulations of Drug Transporter Activity, Localization and Expression. Int J Mol Sci 2017; 18:ijms18040764. [PMID: 28375174 PMCID: PMC5412348 DOI: 10.3390/ijms18040764] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 03/25/2017] [Accepted: 03/27/2017] [Indexed: 01/05/2023] Open
Abstract
Drug transporters are now recognized as major actors in pharmacokinetics, involved notably in drug–drug interactions and drug adverse effects. Factors that govern their activity, localization and expression are therefore important to consider. In the present review, the implications of protein kinases C (PKCs) in transporter regulations are summarized and discussed. Both solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters can be regulated by PKCs-related signaling pathways. PKCs thus target activity, membrane localization and/or expression level of major influx and efflux drug transporters, in various normal and pathological types of cells and tissues, often in a PKC isoform-specific manner. PKCs are notably implicated in membrane insertion of bile acid transporters in liver and, in this way, are thought to contribute to cholestatic or choleretic effects of endogenous compounds or drugs. The exact clinical relevance of PKCs-related regulation of drug transporters in terms of drug resistance, pharmacokinetics, drug–drug interactions and drug toxicity remains however to be precisely determined. This issue is likely important to consider in the context of the development of new drugs targeting PKCs-mediated signaling pathways, for treating notably cancers, diabetes or psychiatric disorders.
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van Eis MJ, Evenou J, Schuler W, Zenke G, Vangrevelinghe E, Wagner J, von Matt P. Indolyl-naphthyl-maleimides as potent and selective inhibitors of protein kinase C-α/β. Bioorg Med Chem Lett 2017; 27:781-786. [DOI: 10.1016/j.bmcl.2017.01.038] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 01/09/2017] [Accepted: 01/12/2017] [Indexed: 12/11/2022]
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Byerly J, Halstead-Nussloch G, Ito K, Katsyv I, Irie HY. PRKCQ promotes oncogenic growth and anoikis resistance of a subset of triple-negative breast cancer cells. Breast Cancer Res 2016; 18:95. [PMID: 27663795 PMCID: PMC5034539 DOI: 10.1186/s13058-016-0749-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 08/20/2016] [Indexed: 12/02/2022] Open
Abstract
Background The protein kinase C (PKC) family comprises distinct classes of proteins, many of which are implicated in diverse cellular functions. Protein tyrosine kinase C theta isoform (PRKCQ)/PKCθ, a member of the novel PKC family, may have a distinct isoform-specific role in breast cancer. PKCθ is preferentially expressed in triple-negative breast cancer (TNBC) compared to other breast tumor subtypes. We hypothesized that PRKCQ/PKCθ critically regulates growth and survival of a subset of TNBC cells. Methods To elucidate the role of PRKCQ/PKCθ in regulating growth and anoikis resistance, we used both gain and loss of function to modulate expression of PRKCQ. We enhanced expression of PKCθ (kinase-active or inactive) in non-transformed breast epithelial cells (MCF-10A) and assessed effects on epidermal growth factor (EGF)-independent growth, anoikis, and migration. We downregulated expression of PKCθ in TNBC cells, and determined effects on in vitro and in vivo growth and survival. TNBC cells were also treated with a small molecule inhibitor to assess requirement for PKCθ kinase activity in the growth of TNBC cells. Results PRKCQ/PKCθ can promote oncogenic phenotypes when expressed in non-transformed MCF-10A mammary epithelial cells; PRKCQ/PKCθ enhances anchorage-independent survival, growth-factor-independent proliferation, and migration. PKCθ expression promotes retinoblastoma (Rb) phosphorylation and cell-cycle progression under growth factor-deprived conditions that typically induce cell-cycle arrest of MCF-10A breast epithelial cells. Proliferation and Rb phosphorylation are dependent on PKCθ-stimulated extracellular signal-related kinase (Erk)/mitogen-activated protein kinase (MAPK) activity. Enhanced Erk/MAPK activity is dependent on the kinase activity of PKCθ, as overexpression of kinase-inactive PKCθ does not stimulate Erk/MAPK or Rb phosphorylation or promote growth-factor-independent proliferation. Downregulation of PRKCQ/PKCθ in TNBC cells enhances anoikis, inhibits growth in 3-D MatrigelTM cultures, and impairs triple-negative tumor xenograft growth. AEB071, an inhibitor of PKCθ kinase activity, also inhibits growth and invasive branching of TNBC cells in 3-D cultures, further supporting a role for PKCθ kinase activity in triple-negative cancer cell growth. Conclusions Enhanced PRKCQ/PKCθ expression can promote growth-factor-independent growth, anoikis resistance, and migration. PRKCQ critically regulates growth and survival of a subset of TNBC. Inhibition of PKCθ kinase activity may be an attractive therapeutic approach for TNBC, a subtype in need of improved targeted therapies. Electronic supplementary material The online version of this article (doi:10.1186/s13058-016-0749-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jessica Byerly
- Division of Hematology and Medical Oncology, Department of Medicine and Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY, USA
| | - Gwyneth Halstead-Nussloch
- Division of Hematology and Medical Oncology, Department of Medicine and Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY, USA
| | - Koichi Ito
- Division of Hematology and Medical Oncology, Department of Medicine and Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY, USA
| | - Igor Katsyv
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Hanna Y Irie
- Division of Hematology and Medical Oncology, Department of Medicine and Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY, USA. .,Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY, USA.
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Abstract
The protein kinase C (PKC) family, discovered in the late 1970s, is composed of at least 10 serine/threonine kinases, divided into three groups based on their molecular architecture and cofactor requirements. PKC enzymes have been conserved throughout evolution and are expressed in virtually all cell types; they represent critical signal transducers regulating cell activation, differentiation, proliferation, death, and effector functions. PKC family members play important roles in a diverse array of hematopoietic and immune responses. This review covers the discovery and history of this enzyme family, discusses the roles of PKC enzymes in the development and effector functions of major hematopoietic and immune cell types, and points out gaps in our knowledge, which should ignite interest and further exploration, ultimately leading to better understanding of this enzyme family and, above all, its role in the many facets of the immune system.
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Affiliation(s)
- Amnon Altman
- Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037; ,
| | - Kok-Fai Kong
- Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037; ,
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Rauert-Wunderlich H, Rudelius M, Ott G, Rosenwald A. Targeting protein kinase C in mantle cell lymphoma. Br J Haematol 2016; 173:394-403. [PMID: 26914495 DOI: 10.1111/bjh.13973] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 12/21/2015] [Indexed: 12/18/2022]
Abstract
Although targeting the Bruton tyrosine kinase (BTK) with ibrutinib has changed lymphoma treatment, patients with mantle cell lymphoma (MCL) remain incurable. In this study, we characterized a broad range of MCL cell lines and primary MCL cells with respect to the response to the BTK inhibitor, ibrutinib, and compared it with the response to the protein kinase C (PKC) inhibitor, sotrastaurin. At clinically relevant concentrations, each drug induced potent cell death only in the REC-1 cell line, which was accompanied by robust inhibition of AKT and ERK1/ERK2 (ERK1/2, also termed MAPK3/MAPK1) phosphorylation. In sensitive REC-1 cells, the drug-mediated impaired phosphorylation was obvious on the levels of B-cell receptor-induced and basal phosphorylation. Similar results were obtained in primary MCL cells with ibrutinib and in a subset with sotrastaurin. The various drug-resistant MCL cell lines showed very distinct responses in terms of basal AKT and ERK1/2 phosphorylation. Interestingly, targeting PKC and BTK at the same time led to ibrutinib-mediated rescue of a weak sotrastaurin-induced apoptosis in MINO cells. Additional targeting of AKT sensitized MINO cells to inhibitor-mediated cytotoxicity. In summary, MCL cells are heterogeneous in their response to BTK or PKC inhibition, indicating the need for even more individualized targeted treatment approaches in subsets of MCL patients.
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Affiliation(s)
- Hilka Rauert-Wunderlich
- Institute of Pathology, University of Würzburg and Comprehensive Cancer Center (CCC) Mainfranken, Würzburg, Germany
| | - Martina Rudelius
- Institute of Pathology, University of Würzburg and Comprehensive Cancer Center (CCC) Mainfranken, Würzburg, Germany
| | - German Ott
- Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany.,Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
| | - Andreas Rosenwald
- Institute of Pathology, University of Würzburg and Comprehensive Cancer Center (CCC) Mainfranken, Würzburg, Germany
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Mahajan VK. Psoriasis treatment: Unconventional and non-standard modalities in the era of biologics. World J Dermatol 2016; 5:17-51. [DOI: 10.5314/wjd.v5.i1.17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Revised: 10/25/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
Psoriasis is a potentially debilitating inflammatory dermatosis affecting 0.2%-4.8% of the population worldwide causing a significant occupational, personal or psychosocial morbidity to these patients for life. The basic aim of psoriasis therapy is to control the disease to maximum possible extent and improve the patient’s quality of life. Management of triggers for flare-ups, lifestyle modifications, and dietary supplements are often recommended. Intermittent or rotational therapy with frequent alterations in treatment options is usually needed to reduce toxicity of anti-psoriatic drugs in the absence of safer alternatives. Currently, several biological agents categorized as either T-cell targeted (e.g., Alefacept, Efalizumab) or cytokine modulating (e.g., Adalimumab, Infliximab, Etanercept) are available for treating severe psoriasis. However, their high cost is often precluding for most patients. The usefulness of systemic (methotrexate, cyclosporine, acitretin or several other therapeutic agents) or topical (tar, anthralin, corticosteroids or calcipotriol ointments, phototherapy with or without psoralens) therapies has been well established for the management of psoriasis. The literature is also replete with benefits of less used non-standard and unconventional treatment modalities (hydroxycarbamide, azathioprine, leflunomide, mycophenolate mofetil, isotretinoin, fumarates, topical calcineurin inhibitors, peroxisome proliferator-activated receptors agonists, statins, sulfasalazine, pentoxifylline, colchicine, grenz ray therapy, excimer laser, climatotherapy and balneophototherapy, peritoneal dialysis, tonsillectomy, ichthyotherapy, etc.). These can be used alternatively to treat psoriasis patients who have mild/minimal lesions, are intolerant to conventional drugs, have developed side effects or achieved recommended cumulative dose, where comorbidities pose unusual therapeutic challenges, or may be as intermittent, rotational or combination treatment alternatives.
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Brezar V, Tu WJ, Seddiki N. PKC-Theta in Regulatory and Effector T-cell Functions. Front Immunol 2015; 6:530. [PMID: 26528291 PMCID: PMC4602307 DOI: 10.3389/fimmu.2015.00530] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 09/28/2015] [Indexed: 01/20/2023] Open
Abstract
One of the major goals in immunology research is to understand the regulatory mechanisms that underpin the rapid switch on/off of robust and efficient effector (Teffs) or regulatory (Tregs) T-cell responses. Understanding the molecular mechanisms underlying the regulation of such responses is critical for the development of effective therapies. T-cell activation involves the engagement of T-cell receptor and co-stimulatory signals, but the subsequent recruitment of serine/threonine-specific protein Kinase C-theta (PKC-θ) to the immunological synapse (IS) is instrumental for the formation of signaling complexes, which ultimately lead to a transcriptional network in T cells. Recent studies demonstrated that major differences between Teffs and Tregs occurred at the IS where its formation induces altered signaling pathways in Tregs. These pathways are characterized by reduced recruitment of PKC-θ, suggesting that PKC-θ inhibits Tregs suppressive function in a negative feedback loop. As the balance of Teffs and Tregs has been shown to be central in several diseases, it was not surprising that some studies revealed that PKC-θ plays a major role in the regulation of this balance. This review will examine recent knowledge on the role of PKC-θ in T-cell transcriptional responses and how this protein can impact on the function of both Tregs and Teffs.
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Affiliation(s)
- Vedran Brezar
- INSERM U955, Équipe 16 and Faculté de Médecine, Université Paris Est , Créteil , France ; Vaccine Research Institute (VRI) , Créteil , France
| | - Wen Juan Tu
- Faculty of Education, Science, Technology and Maths, University of Canberra , Canberra, ACT , Australia
| | - Nabila Seddiki
- INSERM U955, Équipe 16 and Faculté de Médecine, Université Paris Est , Créteil , France ; Vaccine Research Institute (VRI) , Créteil , France
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Lim PS, Sutton CR, Rao S. Protein kinase C in the immune system: from signalling to chromatin regulation. Immunology 2015; 146:508-22. [PMID: 26194700 DOI: 10.1111/imm.12510] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 06/29/2015] [Accepted: 07/15/2015] [Indexed: 12/12/2022] Open
Abstract
Protein kinase C (PKC) form a key family of enzymes involved in signalling pathways that specifically phosphorylates substrates at serine/threonine residues. Phosphorylation by PKC is important in regulating a variety of cellular events such as cell proliferation and the regulation of gene expression. In the immune system, PKCs are involved in regulating signal transduction pathways important for both innate and adaptive immunity, ultimately resulting in the expression of key immune genes. PKCs act as mediators during immune cell signalling through the immunological synapse. PKCs are traditionally known to be cytoplasmic signal transducers and are well embedded in the signalling pathways of cells to mediate the cells' response to a stimulus from the plasma membrane to the nucleus. PKCs are also found to transduce signals within the nucleus, a process that is distinct from the cytoplasmic signalling pathway. There is now growing evidence suggesting that PKC can directly regulate gene expression programmes through a non-traditional role as nuclear kinases. In this review, we will focus on the role of PKCs as key cytoplasmic signal transducers in immune cell signalling, as well as its role in nuclear signal transduction. We will also highlight recent evidence for its newly discovered regulatory role in the nucleus as a chromatin-associated kinase.
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Affiliation(s)
- Pek Siew Lim
- Discipline of Biomedical Sciences, Faculty of Applied Science, University of Canberra, Canberra, ACT, Australia
| | - Christopher Ray Sutton
- Discipline of Biomedical Sciences, Faculty of Applied Science, University of Canberra, Canberra, ACT, Australia
| | - Sudha Rao
- Discipline of Biomedical Sciences, Faculty of Applied Science, University of Canberra, Canberra, ACT, Australia
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Torres T, Filipe P. Small Molecules in the Treatment of Psoriasis. Drug Dev Res 2015; 76:215-27. [DOI: 10.1002/ddr.21263] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 07/14/2015] [Indexed: 12/27/2022]
Affiliation(s)
- Tiago Torres
- Department of Dermatology; Centro Hospitalar do Porto; Portugal
- Instituto de Ciências Biomédicas Abel Salazar; University of Porto; Portugal
| | - Paulo Filipe
- Dermatology Research Unit, Instituto de Medicina Molecular; University of Lisbon; Portugal
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Fukahori H, Chida N, Maeda M, Tasaki M, Kawashima T, Noto T, Tsujimoto S, Nakamura K, Oshima S, Hirose J, Higashi Y, Morokata T. Effect of novel PKCθ selective inhibitor AS2521780 on acute rejection in rat and non-human primate models of transplantation. Int Immunopharmacol 2015; 27:232-7. [DOI: 10.1016/j.intimp.2015.06.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 06/04/2015] [Accepted: 06/09/2015] [Indexed: 11/29/2022]
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Abstract
Protein kinase Cθ (PKCθ) is a key enzyme in T-lymphocytes where it plays an important role in signal transduction downstream of the activated T-cell receptor (TCR) and the CD28 co-stimulatory receptor. Antigenic stimulation of T-cells triggers PKCθ translocation to the centre of the immunological synapse (IS) at the contact site between antigen-specific T-cells and antigen-presenting cells (APCs). The IS-residing PKCθ phosphorylates and activates effector molecules that transduce signals into distinct subcellular compartments and activate the transcription factors, nuclear factor κB (NF-κB), nuclear factor of activated T-cells (NFAT) and activating protein 1 (AP-1), which are essential for the induction of T-cell-mediated responses. Besides its major biological role in T-cells, PKCθ is expressed in several additional cell types and is involved in a variety of distinct physiological and pathological phenomena. For example, PKCθ is expressed at high levels in platelets where it regulates signal transduction from distinct surface receptors, and is required for optimal platelet activation and aggregation, as well as haemostasis. In addition, PKCθ is involved in physiological processes regulating insulin resistance and susceptibility to obesity, and is expressed at high levels in gastrointestinal stromal tumours (GISTs), although the functional importance of PKCθ in these processes and cell types is not fully clear. The present article briefly reviews selected topics relevant to the biological roles of PKCθ in health and disease.
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Mease PJ, Armstrong AW. Managing patients with psoriatic disease: the diagnosis and pharmacologic treatment of psoriatic arthritis in patients with psoriasis. Drugs 2015; 74:423-41. [PMID: 24566842 PMCID: PMC3958815 DOI: 10.1007/s40265-014-0191-y] [Citation(s) in RCA: 187] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Psoriatic arthritis (PsA) is a chronic, systemic inflammatory disease. Up to 40 % of patients with psoriasis will go on to develop PsA, usually within 5-10 years of cutaneous disease onset. Both conditions share common pathogenic mechanisms involving genetic and environmental factors. Because psoriasis is typically present for years before PsA-related joint symptoms emerge, dermatologists are in a unique position to detect PsA earlier in the disease process through regular, routine screening of psoriasis patients. Distinguishing clinical features of PsA include co-occurrence of psoriatic skin lesions and nail dystrophy, as well as dactylitis and enthesitis. Patients with PsA are usually seronegative for rheumatoid factor, and radiographs may reveal unique features such as juxta-articular new bone formation and pencil-in-cup deformity. Early treatment of PsA with disease-modifying anti-rheumatic drugs has the potential to slow disease progression and maintain patient quality of life. Optimally, a single therapeutic agent will control both the skin and joint psoriatic symptoms. A number of traditional treatments used to manage psoriasis, such as methotrexate and cyclosporine, are also effective for PsA, but these agents are often inadequately effective, temporary in benefit and associated with significant safety concerns. Biologic anti-tumour necrosis factor agents, such as etanercept, infliximab and adalimumab, are effective for treating patients who have both psoriasis and PsA. However, a substantial number of patients may lose efficacy, have adverse effects or find intravenous or subcutaneous administration inconvenient. Emerging oral treatments, including phosphodiesterase 4 inhibitors, such as apremilast, and new biologics targeting interleukin-17, such as secukinumab, brodalumab and ixekizumab, have shown encouraging clinical results in the treatment of psoriasis and/or PsA. Active and regular collaboration of dermatologists with rheumatologists in managing patients who have psoriasis and PsA is likely to yield more optimal control of psoriatic dermal and joint symptoms, and improve long-term patient outcomes.
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MESH Headings
- Anti-Inflammatory Agents, Non-Steroidal/administration & dosage
- Anti-Inflammatory Agents, Non-Steroidal/adverse effects
- Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
- Antibodies, Monoclonal/administration & dosage
- Antibodies, Monoclonal/adverse effects
- Antibodies, Monoclonal/therapeutic use
- Arthritis, Psoriatic/diagnosis
- Arthritis, Psoriatic/drug therapy
- Arthritis, Psoriatic/genetics
- Arthritis, Psoriatic/immunology
- Clinical Trials as Topic
- Drug Therapy, Combination
- Early Diagnosis
- Glucocorticoids/administration & dosage
- Glucocorticoids/adverse effects
- Glucocorticoids/therapeutic use
- Humans
- Immunosuppressive Agents/administration & dosage
- Immunosuppressive Agents/adverse effects
- Immunosuppressive Agents/therapeutic use
- Practice Guidelines as Topic
- Psoriasis/diagnosis
- Psoriasis/drug therapy
- Psoriasis/genetics
- Psoriasis/immunology
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Affiliation(s)
- Philip J Mease
- Swedish Medical Center and University of Washington, Seattle, WA, USA,
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41
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Kopp T, Riedl E, Bangert C, Bowman EP, Greisenegger E, Horowitz A, Kittler H, Blumenschein WM, McClanahan TK, Marbury T, Zachariae C, Xu D, Hou XS, Mehta A, Zandvliet AS, Montgomery D, van Aarle F, Khalilieh S. Clinical improvement in psoriasis with specific targeting of interleukin-23. Nature 2015; 521:222-6. [PMID: 25754330 DOI: 10.1038/nature14175] [Citation(s) in RCA: 169] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Accepted: 12/23/2014] [Indexed: 02/06/2023]
Abstract
Psoriasis is a chronic inflammatory skin disorder that affects approximately 2-3% of the population worldwide and has severe effects on patients' physical and psychological well-being. The discovery that psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused on the interleukin (IL)-12/23p40 subunit shared by IL-12 and IL-23. Evidence suggests that specific inhibition of IL-23 would result in improvement in psoriasis. Here we evaluate tildrakizumab, a monoclonal antibody that targets the IL-23p19 subunit, in a three-part, randomized, placebo-controlled, sequential, rising multiple-dose phase I study in patients with moderate-to-severe psoriasis to provide clinical proof that specific targeting of IL-23p19 results in symptomatic improvement of disease severity in human subjects. A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg kg(-1) groups by day 196. In part 2, 10 out of 15 subjects in the 3 mg kg(-1) group and 13 out of 14 subjects in the 10 mg kg(-1) group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate-to-severe psoriasis patients as demonstrated by improvements in PASI scores and histological samples.
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Affiliation(s)
- Tamara Kopp
- 1] Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, University of Vienna Medical School, 1090 Vienna, Austria [2] Juvenis Medical Center, 1010 Vienna, Austria
| | - Elisabeth Riedl
- Department of Dermatology, Division of General Dermatology, University of Vienna Medical School, 1090 Vienna, Austria
| | - Christine Bangert
- Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, University of Vienna Medical School, 1090 Vienna, Austria
| | | | - Elli Greisenegger
- Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, University of Vienna Medical School, 1090 Vienna, Austria
| | - Ann Horowitz
- Merck &Co., Inc., Whitehouse Station, New Jersey 08889, USA
| | - Harald Kittler
- Department of Dermatology, Division of General Dermatology, University of Vienna Medical School, 1090 Vienna, Austria
| | | | | | - Thomas Marbury
- Orlando Clinical Research Center, Orlando, Florida 32809, USA
| | - Claus Zachariae
- Department of Dermato-allergology, Gentofte Hospital, University of Copenhagen, Kildegaardsvej 28, DK-2900 Hellerup, Denmark
| | - Danlin Xu
- Merck &Co., Inc., Whitehouse Station, New Jersey 08889, USA
| | | | - Anish Mehta
- Merck &Co., Inc., Whitehouse Station, New Jersey 08889, USA
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42
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Co-signaling molecules in psoriasis pathogenesis: Implications for targeted therapy. Hum Immunol 2015; 76:95-101. [DOI: 10.1016/j.humimm.2015.01.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Revised: 10/15/2014] [Accepted: 01/15/2015] [Indexed: 12/31/2022]
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43
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Verstrepen L, Beyaert R. Receptor proximal kinases in NF-κB signaling as potential therapeutic targets in cancer and inflammation. Biochem Pharmacol 2014; 92:519-29. [PMID: 25449604 DOI: 10.1016/j.bcp.2014.10.017] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Revised: 10/30/2014] [Accepted: 10/30/2014] [Indexed: 01/12/2023]
Abstract
Many signaling pathways leading to activation of transcription factors and gene expression are characterized by phosphorylation events mediated by specific kinases. The transcription factor NF-κB plays a key role in multiple cellular processes, including immune signaling, inflammation, development, proliferation and survival. Dysregulated NF-κB activation is associated with autoimmunity, chronic inflammation and cancer. Activation of NF-κB requires IκB kinase (IKK)α or β, the activity of which is regulated via phosphorylation by specific IKK kinases and by autophosphorylation. Receptor specificity is further obtained by the use of multiple upstream receptor proximal kinases. We review the identities of several IKK regulatory kinases as well as the proposed molecular mechanisms. In addition, we discuss the potential for therapeutic targeting of some of these kinases in the context of inflammatory diseases and cancer.
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Affiliation(s)
- Lynn Verstrepen
- Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Rudi Beyaert
- Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
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44
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45
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George DM, Breinlinger EC, Friedman M, Zhang Y, Wang J, Argiriadi M, Bansal-Pakala P, Barth M, Duignan DB, Honore P, Lang Q, Mittelstadt S, Potin D, Rundell L, Edmunds JJ. Discovery of Selective and Orally Bioavailable Protein Kinase Cθ (PKCθ) Inhibitors from a Fragment Hit. J Med Chem 2014; 58:222-36. [DOI: 10.1021/jm500669m] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Dawn M. George
- AbbVie Bioresearch Center, 381
Plantation Street, Worcester, Massachusetts 01605, United States
| | - Eric C. Breinlinger
- AbbVie Bioresearch Center, 381
Plantation Street, Worcester, Massachusetts 01605, United States
| | - Michael Friedman
- AbbVie Bioresearch Center, 381
Plantation Street, Worcester, Massachusetts 01605, United States
| | - Yang Zhang
- WuXi AppTec (Shanghai) Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China
| | - Jianfei Wang
- WuXi AppTec (Shanghai) Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China
| | - Maria Argiriadi
- AbbVie Bioresearch Center, 381
Plantation Street, Worcester, Massachusetts 01605, United States
| | - Pratima Bansal-Pakala
- AbbVie Bioresearch Center, 381
Plantation Street, Worcester, Massachusetts 01605, United States
| | | | - David B. Duignan
- AbbVie Bioresearch Center, 381
Plantation Street, Worcester, Massachusetts 01605, United States
| | - Prisca Honore
- AbbVie Inc., 1 North Waukegan
Road, North Chicago, Illinois 60064, United States
| | - QingYu Lang
- AbbVie China R&D Center, 5F, North Jin Chuang Building No. 1, 4560 Jinke Road, Pudong New District, Shanghai 201201, P. R. China
| | - Scott Mittelstadt
- AbbVie Inc., 1 North Waukegan
Road, North Chicago, Illinois 60064, United States
| | | | - Lian Rundell
- AbbVie Bioresearch Center, 381
Plantation Street, Worcester, Massachusetts 01605, United States
| | - Jeremy J. Edmunds
- AbbVie Bioresearch Center, 381
Plantation Street, Worcester, Massachusetts 01605, United States
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46
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PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL. Blood 2014; 124:1481-91. [PMID: 25001469 DOI: 10.1182/blood-2014-05-574830] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Targeting B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) has been successful with durable remissions observed with several targeted therapeutics. Protein kinase C-β (PKC-β) is immediately downstream of BCR and has been shown to be essential to CLL cell survival and proliferation in vivo. We therefore evaluated sotrastaurin (AEB071), an orally administered potent PKC inhibitor, on CLL cell survival both in vitro and in vivo. AEB071 shows selective cytotoxicity against B-CLL cells in a dose-dependent manner. Additionally, AEB071 attenuates BCR-mediated survival pathways, inhibits CpG-induced survival and proliferation of CLL cells in vitro, and effectively blocks microenvironment-mediated survival signaling pathways in primary CLL cells. Furthermore, AEB071 alters β-catenin expression, resulting in decreased downstream transcriptional genes as c-Myc, Cyclin D1, and CD44. Lastly, our preliminary in vivo studies indicate beneficial antitumor properties of AEB071 in CLL. Taken together, our results indicate that targeting PKC-β has the potential to disrupt signaling from the microenvironment contributing to CLL cell survival and potentially drug resistance. Future efforts targeting PKC with the PKC inhibitor AEB071 as monotherapy in clinical trials of relapsed and refractory CLL patients are warranted.
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47
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Vella LJ, Andrews MC, Behren A, Cebon J, Woods K. Immune consequences of kinase inhibitors in development, undergoing clinical trials and in current use in melanoma treatment. Expert Rev Clin Immunol 2014; 10:1107-23. [PMID: 24939732 DOI: 10.1586/1744666x.2014.929943] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Metastatic malignant melanoma is a frequently fatal cancer. In recent years substantial therapeutic progress has occurred with the development of targeted kinase inhibitors and immunotherapeutics. Targeted therapies often result in rapid clinical benefit however responses are seldom durable. Immune therapies can result in durable disease control but responses may not be immediate. Optimal cancer therapy requires both rapid and durable cancer control and this can likely best be achieved by combining targeted therapies with immunotherapeutics. To achieve this, a detailed understanding of the immune consequences of the various kinase inhibitors, in development, clinical trial and currently used to treat melanoma is required.
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Affiliation(s)
- Laura J Vella
- Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immuno-biology Laboratory, Heidelberg, VIC 3084, Australia
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48
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de Weerd A, Kho M, Kraaijeveld R, Zuiderwijk J, Weimar W, Baan C. The protein kinase C inhibitor sotrastaurin allows regulatory T cell function. Clin Exp Immunol 2014; 175:296-304. [PMID: 24131367 DOI: 10.1111/cei.12225] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2013] [Indexed: 12/28/2022] Open
Abstract
The novel immunosuppressant sotrastaurin is a selective inhibitor of protein kinase C isoforms that are critical in signalling pathways downstream of the T cell receptor. Sotrastaurin inhibits nuclear factor (NF)-κB, which directly promotes the transcription of forkhead box protein 3 (FoxP3), the key regulator for the development and function of regulatory T cells (Tregs). Our center participated in a randomized trial comparing sotrastaurin (n = 14) and the calcineurin inhibitor Neoral (n = 7) in renal transplant recipients. We conducted ex vivo mixed lymphocyte reaction (MLR) and flow cytometry studies on these patient samples, as well as in vitro studies on samples of blood bank volunteers (n = 38). Treg numbers remained stable after transplantation and correlated with higher trough levels of sotrastaurin (r = 0·68, P = 0·03). A dose-dependent effect of sotrastaurin on alloresponsiveness was observed: the half maximal inhibitory concentration (IC50 ) to inhibit alloactivated T cell proliferation was 45 ng/ml (90 nM). In contrast, Treg function was not affected by sotrastaurin: in the presence of in vitro-added sotrastaurin (50 ng/ml) Tregs suppressed the proliferation of alloactivated T effector cells at a 1:5 ratio by 35 versus 47% in the absence of the drug (P = 0·33). Signal transducer and activator of transcription 5 (STAT)-5 phosphorylation in Tregs remained intact after incubation with sotrastaurin. This potent Treg function was also found in cells of patients treated with sotrastaurin: Tregs inhibited the anti-donor response in MLR by 67% at month 6, which was comparable to pretransplantation (82%). Sotrastaurin is a potent inhibitor of alloreactivity in vitro, while it did not affect Treg function in patients after kidney transplantation.
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Affiliation(s)
- A de Weerd
- Department of Internal Medicine, Erasmus Medical Center Rotterdam, the Netherlands
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49
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Abstract
PURPOSE OF REVIEW Despite their effectiveness, calcineurin inhibitors (CNIs) represent a major obstacle in the improvement of long-term graft survival in transplantation. The identification of new agents to implement CNI-free regimens is the focus of current transplant research. The purpose of this review is to summarize the novel immunosuppressive agents, including details about their mechanisms of action, stages of development, potential benefits and challenges. RECENT FINDINGS Targeting costimulation with belatacept is now an option for controlling the alloimmune response and has proved to be more effective in preserving long-term allograft function than CNIs despite an increased rate of acute rejection in some studies. mTOR inhibitors are also promising with their remarkable antineoplastic properties, though frequent side-effects may limit their broader use. Other agents under development include JAK inhibitors, CD40 blockade and leukocyte adhesion blockers, with unique potential benefits and side-effects in transplantation. SUMMARY Novel immunosuppressive agents are now available for use in CNI-free regimens in solid organ transplantation. Timing of initiation as well as long-term efficacy and safety are questions that remain to be answered in future clinical trials.
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50
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Protein kinase C inhibitors for immune disorders. Drug Discov Today 2014; 19:1217-21. [PMID: 24892801 DOI: 10.1016/j.drudis.2014.05.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 05/14/2014] [Indexed: 12/11/2022]
Abstract
Protein kinase C (PKC) proteins are a group of well-conserved, intracellular signaling enzymes expressed in all cells and tissues, including immune cells. Much of the molecular insight into PKC immunobiology has been gleaned from studies using PKC gene (Prkc) knockout mice and the analysis of different disease models in these animals. More-recent studies have revealed that PKCs also have crucial roles in the pathogenesis of human immune disorders. Therefore, strategies to modulate the functions of PKC enzymes could have a major impact on the treatment and therapies of autoimmune diseases and other immune disorders.
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