Receptors are crucial for converting chemical and environmental signals into cellular responses, making them prime targets in drug discovery, with about 70% of drugs targeting these receptors. Biased signaling, or functional selectivity, has revolutionized drug development by enabling precise modulation of receptor signaling pathways. This concept is more firmly established in G protein-coupled receptor and has now been applied to other receptor types, including ion channels, receptor tyrosine kinases, and nuclear receptors. Advances in structural biology have further refined our understanding of biased signaling. This targeted approach enhances therapeutic efficacy and potentially reduces side effects. Numerous biased drugs have been developed and approved as therapeutics to treat various diseases, demonstrating their significant therapeutic potential. This review provides a comprehensive overview of biased signaling in drug discovery and disease treatment, highlighting recent advancements and exploring the therapeutic potential of these innovative modulators across various diseases.

In hereditary papillary renal cell carcinoma (HPRCC), the hepatocyte growth factor receptor (MET) receptor tyrosine kinase (RTK) mutations recorded to date are located in the kinase domain and lead to constitutive MET activation. This contrasts with MET mutations identified in non-small cell lung cancer (NSCLC), which lead to exon 14 skipping and deletion of a regulatory domain: in this latter case, the mutated receptor still requires ligand stimulation. Sequencing of MET in samples from 158 HPRCC and 2808 NSCLC patients revealed ten uncharacterized mutations. Four of these, all found in HPRCC and leading to amino acid substitutions in the N-lobe of the MET kinase, proved able to induce cell transformation, which was further enhanced by hepatocyte growth factor (HGF) stimulation: His1086Leu, Ile1102Thr, Leu1130Ser and Cis1125Gly. Similar to the variant resulting in MET exon 14 skipping, the two N-lobe MET variants His1086Leu and Ile1102Thr were found to require stimulation by HGF in order to strongly activate downstream signaling pathways and epithelial cell motility. The Ile1102Thr mutation also displayed transforming potential, promoting tumor growth in a xenograft model. In addition, the N-lobe-mutated MET variants were found to trigger a common HGF-stimulation-dependent transcriptional program, consistent with an observed increase in cell motility and invasion. Altogether, this functional characterization revealed that N-lobe variants still require ligand stimulation, in contrast to other RTK variants. This suggests that HGF expression in the tumor microenvironment is important for tumor growth. The sensitivity of these variants to MET inhibitors opens the way for use of targeted therapies for patients harboring the corresponding mutations.

Sustaining proliferation signaling is the top hallmarks of cancer, driving continuous tumor growth and resistance to drug treatments. Blocking proliferation signaling has shown limited benefit in clinical treatment of pancreatic ductal adenocarcinoma, highlighting the urgent need to deeply understand proliferation signaling and develop new therapeutic strategies.

By leveraging clinical data and data from the TCGA and GDSC datasets, we investigated the association between MMP-28 expression and the sensitivity to EGFR inhibitors as well as the prognosis of PDAC. Transcriptomic and biological experiments explore the regulatory role of MMP-28 on the EGFR signaling pathway. Additionally, in vitro and in vivo studies are employed to evaluate MMP-28 as a biomarker for sensitivity to EGFR inhibitors.

We found that MMP-28, a metalloproteinase, was significantly associated with the sensitivity to EGFR inhibitors. Furthermore, MMP-28 could promote PDAC growth and metastasis. Mechanistically, MMP-28 facilitated the maturation and release of the TGF-α precursor, thus promoting EGFR activation. In return, EGFR upregulated MMP-28 through AP-1-mediated transcription, forming a positive feedback loop that provided sustaining proliferation signaling for PDAC. Subsequently, MMP-28 was identified to predict the response to EGFR inhibitors and recognize responsive patients.

Our findings revealed the role of MMP-28 and EGFR in generation of sustaining proliferation signaling and provided a new therapy strategy for PDAC.

In hereditary papillary renal cell carcinoma (HPRCC), the hepatocyte growth factor receptor (MET) receptor tyrosine kinase (RTK) mutations recorded to date are located in the kinase domain and lead to constitutive MET activation. This contrasts with MET mutations identified in non-small-cell lung cancer (NSCLC), which lead to exon 14 skipping and deletion of a regulatory domain: In this latter case, the mutated receptor still requires ligand stimulation. Sequencing of MET in samples from 158 HPRCC and 2808 NSCLC patients revealed 10 uncharacterized mutations. Four of these, all found in HPRCC and leading to amino acid substitutions in the N-lobe of the MET kinase, proved able to induce cell transformation, which was further enhanced by hepatocyte growth factor (HGF) stimulation: His1086Leu, Ile1102Thr, Leu1130Ser, and Cis1125Gly. Similar to the variant resulting in MET exon 14 skipping, the two N-lobe MET variants His1086Leu and Ile1102Thr were found to require stimulation by HGF in order to strongly activate downstream signaling pathways and epithelial cell motility. The Ile1102Thr mutation also displayed transforming potential, promoting tumor growth in a xenograft model. In addition, the N-lobe-mutated MET variants were found to trigger a common HGF-stimulation-dependent transcriptional program, consistent with an observed increase in cell motility and invasion. Altogether, this functional characterization revealed that N-lobe variants still require ligand stimulation, in contrast to other RTK variants. This suggests that HGF expression in the tumor microenvironment is important for tumor growth. The sensitivity of these variants to MET inhibitors opens the way for use of targeted therapies for patients harboring the corresponding mutations.

Cancer, a leading global cause of death, presents considerable treatment challenges due to resistance to conventional therapies like chemotherapy and radiotherapy. Cyclin-dependent kinase 11 (CDK11), which plays a pivotal role in cell cycle regulation and transcription, is overexpressed in various cancers and is linked to poor prognosis. This study focused on identifying potential inhibitors of CDK11 using computational drug discovery methods. Techniques such as pharmacophore modeling, virtual screening, molecular docking, ADMET predictions, molecular dynamics simulations, and binding free energy analysis were applied to screen a large natural product database. Three pharmacophore models were validated, leading to the identification of several promising compounds with stronger binding affinities than the reference inhibitor. ADMET profiling indicated favorable drug-like properties, while molecular dynamics simulations confirmed the stability and favorable interactions of top candidates with CDK11. Binding free energy calculations further revealed that UNPD29888 exhibited the strongest binding affinity. In conclusion, the identified compound shows potential as a CDK11 inhibitor based on computational predictions, suggesting their future application in cancer treatment by targeting CDK11. These computational findings encourage further experimental validation as anti-cancer agents.

Acute myeloid leukemia (AML), a heterogeneous hematologic malignancy, has generally a poor prognosis despite the recent advancements in diagnostics and treatment. Genetic instability, particularly mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, is associated with severe outcomes. Approximately 30 % of AML patients harbor FLT3 mutations, which have been linked to higher relapse and reduced survival rates. Traditional AML treatments employ cytarabine and anthracyclines drugs. Furthermore, the development of FLT3 inhibitors has significantly improved therapy for FLT3-mutated AML patients. For example, the introduction of midostaurin, the first FLT3 inhibitor, improved patient outcomes. However, resistant AML cell clones continue to pose a challenge to the success of AML treatment. This review discusses FLT3 kinase, mutations, and role in AML pathogenesis. It explores the molecular mechanisms of FLT3 activation, signaling pathways, and the structure and function of the FLT3 receptor. Current and emerging therapeutic approaches are presented, while highlighting the latest FLT3 inhibitors in clinical use, and strategies to overcome drug resistance. Future directions, including personalized therapies and novel drug designs, are examined to provide updated insights into FLT3-targeted treatments. This comprehensive review aims to guide clinicians and researchers in the development of innovative therapies to improve AML patient outcomes.

Receptor tyrosine kinases (RTKs) are potent oncoproteins in cancer that, when mutated or overexpressed, can cause uncontrolled growth of cells, angiogenesis, and metastasis, making them significant targets for cancer treatment. Vascular endothelial growth factor receptor 2 (VEGFR2), is a tyrosine kinase receptor that is produced in endothelial cells and is the most crucial regulator of angiogenic factors involved in tumor angiogenesis. So, a series of new substituted N-(4-((2-aminopyrimidin-5-yl)oxy)phenyl)-N-phenyl cyclopropane- 1,1-dicarboxamide derivatives as VEGFR-2 inhibitors have been designed and synthesized.

Utilizing H-NMR, C13-NMR, and mass spectroscopy, the proposed derivatives were produced and assessed. HT-29 and COLO-205 cell lines were used for the cytotoxicity tests. The effective compound was investigated further for the Vegfr-2 kinase inhibition assay, cell cycle arrest, and apoptosis. A molecular docking examination was also carried out with the Maestro-12.5v of Schrodinger.

In comparison to the reference drug Cabozantinib (IC50 = 9.10 and 10.66 μM), compound SP2 revealed promising cytotoxic activity (IC50 = 4.07 and 4.98 μM) against HT-29 and COLO-205, respectively. The synthesized compound SP2 showed VEGFR-2 kinase inhibition activity with (IC50 = 6.82 μM) against the reference drug, Cabozantinib (IC50 = 0.045 μM). Moreover, compound SP2 strongly induced apoptosis by arresting the cell cycle in the G1 phase. The new compounds' potent VEGFR-2 inhibitory effect was noted with key amino acids Asp1044, and Glu883, and the hydrophobic interaction was also observed in the pocket of the VEGFR-2 active site by using a docking study.

The results demonstrate that at the cellular and enzyme levels, the synthetic compounds SP2 are similarly effective as cabozantinib. The cell cycle and apoptosis data demonstrate the effectiveness of the suggested compounds. Based on the findings of docking studies, cytotoxic effects, in vitro VEGFR-2 inhibition, apoptosis, and cell cycle arrest, this research has given us identical or more effective VEGFR-2 inhibitors.

The extensive heterogeneity and the limited availability of effective targeted therapies contribute to the challenging prognosis and restricted survival observed in triple-negative breast cancer (TNBC). Recent research indicates the aberrant expression of diverse tyrosine kinases (TKs) within this cancer, contributing significantly to tumor cell proliferation, survival, invasion, and migration. The contemporary paradigm shift towards precision medicine has highlighted TKs and their receptors as promising targets for pharmacotherapy against a range of malignancies, given their pivotal roles in tumor initiation, progression, and advancement. Intensive investigations have focused on various monoclonal antibodies (mAbs) and small molecule inhibitors that specifically target proteins such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), cellular mesenchymal-epithelial transition factor (c-MET), human epidermal growth factor receptor 2 (HER2), among others, for combating TNBC. These agents have been studied both in monotherapy and in combination with other chemotherapeutic agents. Despite these advances, a substantial terrain of unexplored potential lies within the realm of TK targeted therapeutics, which hold promise in reshaping the therapeutic landscape. This review summarizes the various TK targeted therapeutics that have undergone scrutiny as potential therapeutic interventions for TNBC, dissecting the outcomes and revelations stemming from diverse clinical investigations. A key conclusion from the umbrella clinical trials evidences the necessity for in-depth molecular characterization of TNBCs for the maximum efficiency of TK targeted therapeutics, either as standalone treatments or a combination. Moreover, our observation highlights that the outcomes of TK targeted therapeutics in TNBC are substantially influenced by the diversity of the patient cohort, emphasizing the prioritization of individual patient genetic/molecular profiles for precise TNBC patient stratification for clinical studies.

Sevenless (Sev) is a Drosophila receptor tyrosine kinase (RTK) required for the specification of the R7 photoreceptor. It is cleaved into α and β subunits and binds the ectodomain of the G-protein-coupled receptor bride of sevenless (Boss). Previous work showed that the Boss ectodomain could bind but not activate Sev; rather, the whole seven-pass transmembrane Boss was required. Here, we show that Sev does not need to be cleaved to function and that a single-pass transmembrane form of Boss activates Sev. We use cryo-electron microscopy and biophysical methods to determine the structural basis of ligand binding and pH-dependent dimerization of Sev, and we discuss the implications in the process of Sev activation. The Sev human homolog, receptor oncogene from sarcoma 1 (ROS1), is associated with oncogenic transformations, and we discuss their structural similarities.

Morphine has a crucial role in treating both moderate to severe pain and chronic pain. However, prolonged administration of morphine can lead to tolerance of analgesia, resulting in increased doses and poor treatment of pain. Many patients, such as those with terminal cancer, require high doses of morphine for long periods. Addressing morphine tolerance can help this group of patients to escape pain, and the mechanisms behind this need to be investigated. Microglia are the key cells involved in morphine tolerance and chronic morphine administration leads to microglia activation, which in turn leads to activation of internal microglia signalling pathways and protein transcription, ultimately leading to the release of inflammatory factors. Inhibiting the activation of microglia internal signalling pathways can reduce morphine tolerance. However, the exact mechanism of how morphine acts on microglia and ultimately leads to tolerance is unknown. This article discusses the mechanisms of morphine induced microglia activation, reviews the signalling pathways within microglia and the associated therapeutic targets and possible drugs, and provides possible directions for clinical prevention or retardation of morphine induced analgesic tolerance.

The complex neuronal architecture and the long distance of synapses from the cell body require precisely orchestrated axonal and dendritic transport processes to support key neuronal functions including synaptic signalling, learning and memory formation. Protein phosphorylation is a major regulator of both intracellular transport and synaptic functions. Some kinases and phosphatases such as cyclin dependent kinase-5 (cdk5)/p35, glycogen synthase kinase-3β (GSK3β) and protein phosphatase-1 (PP1) are strongly involved in these processes. A primary pathological hallmark of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal dementia, is synaptic degeneration together with disrupted intracellular transport. One attractive possibility is that alterations to key kinases and phosphatases may underlie both synaptic and axonal transport damages. The brain enriched lemur tail kinases (LMTKs, formerly known as lemur tyrosine kinases) are involved in intracellular transport and synaptic functions, and are also centrally placed in cdk5/p35, GSK3β and PP1 signalling pathways. Loss of LMTKs is documented in major neurodegenerative diseases and thus can contribute to pathological defects in these disorders. However, whilst function of their signalling partners became clearer in modulating both synaptic signalling and axonal transport progress has only recently been made around LMTKs. In this review, we describe this progress with a special focus on intracellular transport, synaptic functions and neurodegenerative diseases.

1,3,5-Triazine scaffold has garnered considerable interest due to its wide-ranging pharmacological properties, particularly in the field of cancer research. Breast cancer is the most commonly diagnosed cancer among women. Approximately one in eight women will receive a diagnosis of invasive breast cancer during their lifetime. The five-year survival rate for invasive breast cancer is less than 30 %, indicating a need to develop a more effective therapeutic agent targeting breast cancer. This review discusses bioactive 1,3,5-triazines targeting breast cancer cells by the inhibition of different enzymes, which include PI3K, mTOR, EGFR, VEGFR, FAK, CDK, DHFR, DNA topoisomerase, ubiquitin-conjugating enzyme, carbonic anhydrase, and matrix metalloproteinase. The anticancer agent search in some drug discovery programs is based on compound screening for antiproliferative activity. Often, multiple targets contribute to the anticancer effect of 1,3,5-triazines and this approach allows identification of active molecules prior to identification of their targets.

Breast cancer is a multifactorial disease driven by acquired genetic and epigenetic changes that lead to aberrant regulation of cellular signaling pathways. Receptor tyrosine kinases (RTKs), a class of critical receptors, are involved in the initiation and progression of breast cancer. RTKs are cell surface receptors with unique structures and biological characteristics, which respond to environmental signals by initiating signaling cascades such as the mitogen-activated protein kinase (MAPK) pathway, Janus kinase (JAK)/signal transducer, activator of transcription (STAT) pathway, and phosphoinositide 3-kinase (PI3K)/AKT pathway. The critical role of RTKs makes them suitable targets for breast cancer treatment. Targeted therapies against RTKs have been developed in recent years, evaluated in clinical trials, and approved for several cancer types, including breast cancer. However, breast cancer displays molecular heterogeneity and exhibits different therapeutic responses to various drug types, leading to limited effectiveness of targeted therapy against RTKs. In this review, we summarize the structural and functional characteristics of selected RTKs and discuss the mechanisms and current status of drug therapy involving different protein tyrosine kinases in breast cancer progression.

During the past two decades, significant advances have been made in the discovery and development of targeted inhibitors aimed at improving the survival rates of cancer patients. Among the multitude of potential therapeutic targets identified thus far, Receptor Tyrosine Kinases (RTKs) are of particular importance. Dysregulation of RTKs has been implicated in numerous human diseases, particularly cancer, where aberrant signaling pathways contribute to disease progression. RTKs have a profound impact on intra and intercellular communication, and they also facilitate post-translational modifications, notably phosphorylation, which intricately regulates a multitude of cellular processes. Prolonged phosphorylation or the disruption of kinase regulation may lead to significant alterations in cell signaling. The emergence of small molecule kinase inhibitors has revolutionized cancer therapy by offering a targeted and strategic approach that surpasses the efficacy of traditional chemotherapeutic drugs. Over the last two decades, a plethora of targeted inhibitors have been identified or engineered and have undergone clinical evaluation to enhance the survival rates of cancer patients. In this review, we have compared the expression of different RTKs, including Met, KDR/VEGFR2, EGFR, BRAF, BCR, and ALK across different cancer types in TCGA samples. Additionally, we have summarized the recent development of small molecule inhibitors and their potential in treating various malignancies. Lastly, we have discussed the mechanisms of acquired therapeutic resistance with a focus on kinase inhibitors in EGFR mutant and ALK-rearranged non-small cell lung cancer and BCR-ABL positive chronic myeloid leukemia.

Tyrosine kinase inhibitor (TKI)-targeted therapy has revolutionized cancer treatment by selectively blocking specific signaling pathways crucial for tumor growth, offering improved outcomes with fewer side effects compared with conventional chemotherapy. However, despite their initial effectiveness, resistance to TKIs remains a significant challenge in clinical practice. Understanding the mechanisms underlying TKI resistance is paramount for improving patient outcomes and developing more effective treatment strategies. In this review, we explored various mechanisms contributing to TKI resistance, including on-target mechanisms and off-target mechanisms, as well as changes in the tumor histology and tumor microenvironment (intrinsic mechanisms). Additionally, we summarized current therapeutic approaches aiming at circumventing TKI resistance, including the development of next-generation TKIs and combination therapies. We also discussed emerging strategies such as the use of dual-targeted antibodies and PROteolysis Targeting Chimeras. Furthermore, we explored future directions in TKI-targeted therapy, including the methods for detecting and monitoring drug resistance during treatment, identification of novel targets, exploration of dual-acting kinase inhibitors, application of nanotechnologies in targeted therapy, and so on. Overall, this review provides a comprehensive overview of the challenges and opportunities in TKI-targeted therapy, aiming to advance our understanding of resistance mechanisms and guide the development of more effective therapeutic approaches in cancer treatment.

Ligands such as insulin, epidermal growth factor, platelet-derived growth factor, and nerve growth factor (NGF) initiate signals at the cell membrane by binding to receptor tyrosine kinases (RTKs). Along with G-protein-coupled receptors, RTKs are the main platforms for transducing extracellular signals into intracellular signals. Studying RTK signaling has been a challenge, however, due to the multiple signaling pathways to which RTKs typically are coupled, including MAP/ERK, PLCγ, and Class 1A phosphoinositide 3-kinases (PI3K). The multi-pronged RTK signaling has been a barrier to isolating the effects of any one downstream pathway. Here, we used optogenetic activation of PI3K to decouple its activation from other RTK signaling pathways. In this context, we used genetic code expansion to introduce a click chemistry noncanonical amino acid into the extracellular side of membrane proteins. Applying a cell-impermeant click chemistry fluorophore allowed us to visualize delivery of membrane proteins to the plasma membrane in real time. Using these approaches, we demonstrate that activation of PI3K, without activating other pathways downstream of RTK signaling, is sufficient to traffic the TRPV1 ion channels and insulin receptors to the plasma membrane.

Tropomyosin (TPM) is an important regulatory protein that binds to actin in fine myofilaments, playing a crucial role in the regulation of muscle contraction. TPM3, as one of four tropomyosin genes, is notably prevalent in eukaryotic cells. Traditionally, abnormal gene expression of TPM3 has been exclusively associated with myopathy. However, recent years have witnessed a surge in studies highlighting the close correlation between abnormal expression of TPM3 and the onset, progression, metastasis, and prognosis of various malignant tumors. In light of this, investigating the mechanisms underlying the pathogenetic role of TPM3 holds significant promise for early diagnosis and more effective treatment strategies. This article aims to provide an insightful review of the structural characteristics of TPM3 and its intricate role in the occurrence and development of malignant tumors.

Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.

Tyrosine kinase inhibitors (TKIs) have demonstrated significant efficacy against various types of cancers through molecular targeting mechanisms. Over the past 22 years, more than 100 TKIs have been approved for the treatment of various types of cancer indicating the significant progress achieved in this research area. Despite having significant efficacy and ability to target multiple pathways, TKIs administration is associated with challenges. There are reported inconsistencies between observed food effect and labeling administration, challenges of concomitant administration with acid-reducing agents (ARA), pill burden and dosing frequency. In this context, the objective of present review is to visit administration challenges of TKIs and effective ways to tackle them. We have gathered data of 94 TKIs approved in between 2000 and 2022 with respect to food effect, ARA impact, administration schemes (food and PPI restrictions), number of pills per day and administration frequency. Further, trend analysis has been performed to identify inconsistencies in the labeling with respect to observed food effect, molecules exhibiting ARA impact, in order to identify solutions to remove these restrictions through novel formulation approaches. Additionally, opportunities to reduce number of pills per day and dosing frequency for better patient compliance were suggested using innovative formulation interventions. Finally, utility of physiologically based pharmacokinetic modeling (PBPK) for rationale formulation development was discussed with literature reported examples. Overall, this review can act as a ready-to-use-guide for the formulation, biopharmaceutics scientists and medical oncologists to identify opportunities for innovation for TKIs.

High expression of the receptor tyrosine kinase (RTK) insulin-like growth factor-1 receptor (IGF1R) and RTK mutations are associated with high-risk/worse prognosis in multiple myeloma (MM). Combining the pIGF1R/pINSR inhibitor linsitinib with the proteasome inhibitor (PI) bortezomib seemed promising in a clinical trial, but IGF1R expression was not associated with therapy response. Because the oncogenic impact of IGF1R mutations is so far unknown, we investigated the functional impact of IGF1R mutations on survival signaling, viability/proliferation and survival response to therapy. We transfected four human myeloma cell lines (HMCLs) with IGF1RWT, IGF1RD1146N and IGF1RN1129S (Sleeping Beauty), generated CRISPR-Cas9 IGF1R knockouts in the HMCLs U-266 (IGF1RWT) and L-363 (IGF1RD1146N) and tested the anti-MM activity of linsitinib alone and in combination with the second-generation PI carfilzomib in seven HMCLs. IGF1R knockout entailed reduced proliferation. Upon IGF1R overexpression, survival signaling was moderately increased in all HCMLs and slightly affected by IGF1RN1129S in one HMCL, whereby the viability remained unaffected. Expression of IGF1RD1146N reduced pIGF1R-Y1135, especially under serum reduction, but did not impact downstream signaling. Linsitinib and carfilzomib showed enhanced anti-myeloma activity in six out of seven HMCL irrespective of the IGF1R mutation status. In conclusion, IGF1R mutations can impact IGF1R activation and/or downstream signaling, and a combination of linsitinib with carfilzomib might be a suitable therapeutic approach for MM patients potentially responsive to IGF1R blockade.

Crizotinib was approved to treat patients with advanced non-small cell lung cancer (aNSCLC) with ROS proto-oncogene 1 (ROS1) gene fusion in 2016. We conducted a systematic literature review to identify real-world evidence (RWE) studies and estimated the efficacy and safety of crizotinib using meta-analyses (MA) for objective response rate (ORR), real-world progression-free survival (PFS), and overall survival (OS).

We searched MEDLINE®, Embase, and Cochrane CENTRAL from January 2016 to March 2023 using Ovid® for published single-arm or comparative RWE studies evaluating patients (N ≥ 20) receiving crizotinib monotherapy for aNSCLC with ROS1 gene fusion. Pooled estimates for ORR and grade 3/4 adverse events (AEs) were derived using the metafor package in R while pooled estimates for median real-world PFS (rwPFS) and OS were derived using reconstructed individual patient data from published Kaplan-Meier curves. The primary analysis included all studies regardless of crizotinib line of therapy; a subgroup analysis (SA) was conducted using studies evaluating patients receiving first-line crizotinib.

Fourteen studies met the eligibility criteria and were considered feasible for MA. For the primary analysis, the pooled ORR (N = 9 studies) was 70.6 % (95 % confidence interval [CI]: 57.0, 81.3), median rwPFS was 14.5 months (N = 11 studies), and OS was 40.2 months (N = 9 studies). In the SA, the pooled ORR (N = 4 studies) was 81.1 % (95 % CI: 76.1, 85.2) and the median rwPFS (N = 4 studies) and OS (N = 2 studies) were 18.1 and 60 months, respectively. All MAs were associated with significant heterogeneity (I2 > 25 %). Grade 3/4 AEs occurred in 18.7 % of patients (pooled estimate).

The results from this study are consistent with clinical trial data and, taken collectively, supports crizotinib as a safe and effective treatment across different lines of therapy in patients with ROS1 aNSCLC in the real-world setting.

Binding affinity is an important factor in drug design to improve drug-target selectivity and specificity. In this study, in silico techniques based on molecular docking followed by molecular dynamics (MD) simulations were utilized to identify the key residue(s) for CSF1R binding affinity among 14 pan-tyrosine kinase inhibitors and 15 CSF1R-specific inhibitors. We found tryptophan at position 550 (W550) on the CSF1R binding site interacted with the inhibitors' aromatic ring in a π-π way that made the ligands better at binding. Upon W550-Alanine substitution (W550A), the binding affinity of trans-(-)-kusunokinin and imatinib to CSF1R was significantly decreased. However, in terms of structural features, W550 did not significantly affect overall CSF1R structure, but provided destabilizing effect upon mutation. The W550A also did not either cause ligand to change its binding site or conformational changes due to ligand binding. As a result of our findings, the π-π interaction with W550's aromatic ring could be still the choice for increasing binding affinity to CSF1R. Nevertheless, our study showed that the increasing binding to W550 of the design ligand may not ensure CSF1R specificity and inhibition since W550-ligand bound state did not induce significantly conformational change into inactive state.

Tyrosine kinase inhibitors (TKIs) have emerged as a potential treatment strategy for glioblastoma multiforme (GBM). However, their efficacy is limited by various drug resistance mechanisms. To devise more effective treatments for GBM, genetic characteristics must be considered in addition to pre-existing treatments. We performed an integrative analysis with heterogeneous GBM datasets of genomic, transcriptomic, and proteomic data from DepMap, TCGA and CPTAC. We found that poor prognosis was induced by co-upregulation of heat shock protein family A member 5 (HSPA5) and fibroblast growth factor receptor 1 (FGFR1). Co-up regulation of these two genes could regulate the PI3K/AKT pathway. GBM cell lines with co-upregulation of these two genes showed higher drug sensitivity to PI3K inhibitors. In the mesenchymal subtype, the co-upregulation of FGFR1 and HSPA5 resulted in the most malignant subtype of GBM. Furthermore, we found this newly discovered subtype was correlated with homologous recombination deficiency (HRD) In conclusion, we discovered novel druggable candidates within the group exhibiting co-upregulation of these two genes in GBM, suggest potential strategies for combination therapy.

The human genome encodes at least 500 protein kinases, and among them, there are at least 90 tyrosine kinases [...].

Breast cancer is still the largest cause of cancer death in women, and around 70% of primary breast cancer patients are estrogen receptor (ER)-positive, which is the most frequent kind of breast cancer. The lemur tyrosine kinase-3 (LMTK3) receptor has been linked to estrogen responsiveness in breast cancer. However, the function of LMTK3 in reaction to cytotoxic chemotherapy has yet to be studied. Breast cancer therapy research remains tricky due to a paucity of structural investigations on LMTK3. We performed structural investigations on LMTK3 using molecular docking and molecular dynamics (MD) simulations of the LMTK3 receptor in complex with the top three inhibitor molecules along with a control inhibitor. Analysis revealed the top three compounds show the best binding affinities during docking simulations. Interactive analysis of hydrogen bonds inferred hotspot residues Tyr163, Asn138, Asp133, Tyr56, Glu52, Ser132, Asp313, and Asp151. Some other residues in the 5-Å region determined strong alkyl bonds and conventional hydrogen bond linkages. Furthermore, protein dynamics analysis revealed significant modifications among the top complexes and the control system. There was a transition from a loop to a-helix conformation in the protein-top1 complex, and in contrast, in complexes top2 and top3, the formation of a stabilizing sheet in the C chain was observed, which limited significant mobility and increased complex stability. Significant structural alterations were observed in the protein-top complexes, including a shorter helix region and the creation of some loop regions in comparison to the control system. Interestingly, binding free energies, including MMGB/PBSA WaterSwap analysis estimation, reveals that the top1 complex system was more stable than other systems, especially in comparison to the control inhibitor complex system. These results suggest a the plausible mode of action for the novel inhibitors. Therefore, the current investigation contributes to understanding the mechanism of action, serving as a basis for future experimental studies.

Sorafenib is a multikinase inhibitor indicated for first-line treatment of unresectable hepatocellular carcinoma. Despite its widespread use in the clinic, the existing knowledge of sorafenib mode-of-action remains incomplete. To build upon the current understanding, we used the Cellular Thermal Shift Assay (CETSA) coupled to Mass Spectrometry (CETSA-MS) to monitor compound binding to its target proteins in the cellular context on a proteome-wide scale. Among the potential sorafenib targets, we identified aldehyde dehydrogenase 2 (ALDH2), an enzyme that plays a major role in alcohol metabolism. We validated the interaction of sorafenib with ALDH2 by orthogonal methods using pure recombinant protein, proving that this interaction is not mediated by other cellular components. Moreover, we showed that sorafenib inhibits ALDH2 activity, supporting a functional role for this interaction. Finally, we were able to demonstrate that both ALDH2 protein expression and activity were reduced in sorafenib-resistant cells compared to the parental cell line. Overall, our study allowed the identification of ALDH2 as a novel sorafenib target and sheds light on its potential role in both hepatocellular carcinoma and sorafenib resistance condition.

SRC kinase associated phosphoprotein 1 (SKAP1), an adaptor for protein assembly, plays an important role in the immune system such as stabilizing immune synapses. Understanding how these functions are controlled at the level of the protein-protein interactions is necessary to describe these processes and to develop therapeutics. Here, we dissected the SKAP1 modular organization to recognize SRC kinases and compared it to that of its paralog SRC kinase associated phosphoprotein 2 (SKAP2). Different conserved motifs common to either both proteins or specific to SKAP2 were found using this comparison. Two modules harboring different binding properties between SKAP1 and SKAP2 were identified: one composed of two conserved motifs located in the second interdomain interacting at least with the SH2 domain of SRC kinases and a second one composed of the DIM domain modulated by the SH3 domain and the activation of SRC kinases. This work suggests a convergent evolution of the binding properties of some SRC kinases interacting specifically with either SKAP1 or SKAP2.

Growth-factor-receptor-binding protein 2 (GRB2) is a non-enzymatic adaptor protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses, including signaling transduction and gene expression. GRB2 binds to numerous target molecules, thereby modulating a complex cell signaling network with diverse functions. The structural characteristics of GRB2 are essential for its functionality, as its multiple domains and interaction mechanisms underpin its role in cellular biology. The typical signaling pathway involving GRB2 is initiated by the ligand stimulation to its receptor tyrosine kinases (RTKs). The activation of RTKs leads to the recruitment of GRB2 through its SH2 domain to the phosphorylated tyrosine residues on the receptor. GRB2, in turn, binds to the Son of Sevenless (SOS) protein through its SH3 domain. This binding facilitates the activation of Ras, a small GTPase, which triggers a cascade of downstream signaling events, ultimately leading to cell proliferation, survival, and differentiation. Further research and exploration into the structure and function of GRB2 hold great potential for providing novel insights and strategies to enhance medical approaches for related diseases. In this review, we provide an outline of the proteins that engage with domains of GRB2, along with the function of different GRB2 domains in governing cellular signaling pathways. This furnishes essential points of current studies for the forthcoming advancement of therapeutic medications aimed at GRB2.

Cancer is one of the most significant health challenges worldwide. Various techniques, tools and therapeutics/materials have been developed in the last few decades for the treatment of cancer, together with great interest, funding and efforts from the scientific society. However, all the reported studies and efforts seem insufficient to combat the various types of cancer, especially the advanced ones. The overexpression of tyrosine kinases is associated with cancer proliferation and/or metastasis. VEGF, an important category of tyrosine kinases, and its receptors (VEGFR) are hyper-activated in different cancers. Accordingly, they are known as important factors in the angiogenesis of different tumors and are considered in the development of effective therapeutic approaches for controlling many types of cancer. In this case, targeted therapeutic approaches are preferable to the traditional non-selective approaches to minimize the side effects and drawbacks associated with treatment. Several indole-containing compounds have been identified as effective agents against VEGFR. Herein, we present a summary of the recent indolyl analogs reported within the last decade (2012-2023) with potential antineoplastic and VEGFR inhibitory properties. The most important drugs, natural products, synthesized potent compounds and promising hits/leads are highlighted. Indoles functionalized and conjugated with various heterocycles beside spiroindoles are also considered.

VEGFR2 and FAK signaling pathways are interconnected and have synergistic effects on tumor angiogenesis, growth, and metastasis. Thus, instead of the conventional targeting of each of these proteins individually with a specific inhibitor, the present work aimed to discover novel dual inhibitors targeting both VEGFR2 and FAK exploiting their association. To this end, receptor-based pharmacophore modeling technique was opted to generate 3D pharmacophore models for VEGFR2 and FAK type II kinase inhibitors. The generated pharmacophore models were validated by assessing their ability to discriminate between active and decoy compounds in a pre-compiled test set of VEGFR2 and FAK active compounds and decoys. ZINCPharmer web tool was then used to screen the ZINC database purchasable subset using the validated pharmacophore models retrieving 42,616 hits for VEGFR2 and 28,475 hits for FAK. Subsequently, they were filtered using various filters leaving 13,023 and 6,832 survived compounds for VEGFR2 and FAK, respectively, with 124 common compounds. Based on molecular docking simulations, thirteen compounds were found to satisfy all necessary interactions with VEGFR2 and FAK kinase domains. Thus, they are predicted to have a possible dual VEGFR2/FAK inhibitory activity. Finally, SwissADME web tool showed that compound ZINC09875266 is not only promising in terms of binding pattern to our target kinases, but also in terms of pharmacokinetic properties.

Adjusting the microenvironment around the cell surface is critical to responding to external cues or endogenous signals and to maintaining cell activities. In plant cells, the plasma membrane is covered by the cell wall and scaffolded with cytoskeletal networks, which altogether compose the cell surface. It has long been known that these structures mutually interact, but the mechanisms that integrate the whole system are still obscure. Here we spotlight the brassinosteroid (BR) plant hormone receptor BRASSINOSTEROID INSENSITIVE1 (BRI1) since it represents an outstanding model for understanding cell surface signalling and regulation. We summarize how BRI1 activity and dynamics are controlled by plasma membrane components and their associated factors to fine-tune signalling. The downstream signals, in turn, manipulate cell surface structures by transcriptional and post-translational mechanisms. Moreover, the changes in these architectures impact BR signalling, resulting in a feedback loop formation. This Review discusses how BRI1 and BR signalling function as central hubs to integrate cell surface regulation.

Precision oncology and pharmacogenomics (PGx) intersect in their overarching goal to institute the right treatment for the right patient. However, the translation of these innovations into clinical practice is still lagging behind. Therefore, this study aimed to analyze the current state of research and to predict the future directions of applied PGx in the field of precision oncology as represented by the targeted therapy class of tyrosine kinase inhibitors (TKIs). Advanced bibliometric and scientometric analyses of the literature were performed. The Scopus database was used for the search, and articles published between 2001 and 2023 were extracted. Information about productivity, citations, cluster analysis, keyword co-occurrence, trend topics, and thematic evolution were generated. A total of 448 research articles were included in this analysis. A burst of scholarly activity in the field was noted by the year 2005, peaking in 2017, followed by a remarkable decline to date. Research in the field was hallmarked by consistent and impactful international collaboration, with the US leading in terms of most prolific country, institutions, and total link strength. Thematic evolution in the field points in the direction of more specialized studies on applied pharmacokinetics of available and novel TKIs, particularly for the treatment of lung and breast cancers. Our results delineate a significant advancement in the field of PGx in precision oncology. Notwithstanding the practical challenges to these applications at the point of care, further research, standardization, infrastructure development, and informed policymaking are urgently needed to ensure widespread adoption of PGx.

Innate nucleic acid sensing is a ubiquitous and highly conserved immunological process, which is pivotal for monitoring and responding to pathogenic invasion and cellular damage, and central to host defense, autoimmunity, cell fate determination and tumorigenesis. Tyrosine phosphorylation, a major type of post-translational modification, plays a critical regulatory role in innate immune sensing pathway. Core members of nucleic acid sensing signaling pathway, such as cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS), stimulator of interferon genes (STING), and TANK binding kinase 1 (TBK1), are all subject to activity regulation triggered by tyrosine phosphorylation, thereby affecting the host antiviral defense and anti-tumor immunity under physiological or pathological conditions. This review summarizes the recent advances in research on tyrosine kinases and tyrosine phosphorylation in regulation of nucleic acid sensing. The function and potential applications of targeting tyrosine phosphorylation in anti-tumor immunity is disussed to provide insights for understanding and expanding new anti-tumor strategies.

The lemur family of protein kinases has gained much interest in recent years as they are involved in a variety of cellular processes including regulation of axonal transport and endosomal trafficking, modulation of synaptic functions, memory and learning, and they are centrally placed in several intracellular signalling pathways. Numerous studies have also implicated role of the lemur kinases in the development and progression of a wide range of cancers, cystic fibrosis, and neurodegenerative diseases. However, parallel discoveries and inaccurate prediction of their kinase activity have resulted in a confusing and misleading nomenclature of these proteins. Herein, a group of international scientists with expertise in lemur family of protein kinases set forth a novel nomenclature to rectify this problem and ultimately help the scientific community by providing consistent information about these molecules.

Nerve growth factor (NGF) and its receptor, tropomyosin kinase receptor kinase type A (TrkA) is emerging as an important target for Glioblastoma (GBM) treatment. TrkA is the cancer biomarker majorly involved in tumor invasion and migration into nearby normal tissue. However, currently, available Trk inhibitors exhibit many adverse effects in cancer patients, thus demanding a novel class of ligands to regulate Trk signaling. Here, we exploited the role of TrkA (NTRK1) expression from the 651 datasets of brain tumors. RNA sequence analysis identified overexpression of NTRK1 in GBM, recurrent GBM as well in Oligoastrocytoma patients. Also, TrkA expression tends to increase over the higher grades of GBM. TrkA protein targeting hydrazone derivatives, R48, R142, and R234, were designed and their mode of interaction was studied using molecular docking and dynamic simulation studies. Ligands' stability and binding assessment reveals R48, 2 2-(2-(2-hydroxy-4-nitrophenyl) hydrazineylidene)-1-phenylbutane-1,3-dione, as a potent ligand that interacts well with TrkA's hydrophobic residues, Ile, Phe, Leu, Ala, and Val. R48- TrkA exhibits stable binding potentials with an average RMSD value <0.8 nm. R48 obeyed Lipinski's rule of five and possessed the best oral bioavailability, suggesting R48 as a potential compound with drug-likeness properties. In-vitro analysis also revealed that R48 exhibited a higher cytotoxicity effect for U87 GBM cells than TMZ with the IC50 value of 68.99 μM. It showed the lowest percentage of cytotoxicity to the non-cancerous TrkA expressing MEF cells. However, further SiRNA analysis validates the non-specific binding of R48, necessitating structural alteration for the development of R48-based TrkA inhibitor for GBM therapeutics.

Receptor tyrosine kinases (RTKs) serve as molecular targets for the development of novel personalized therapies in many malignancies. In the present study, expression pattern of receptor tyrosine kinases and its clinical significance in orbital RMS has been explored. Eighteen patients with histopathologically confirmed orbital RMS formed part of this study. Comprehensive q-PCR gene expression profiles of 19 RTKs were generated in the cases and controls. The patients were followed up for 59.53 ± 20.93 years. Clustering and statistical analysis tools were applied to identify the significant combination of RTKs associated with orbital rhabdomyosarcoma patients. mRNA overexpression of RTKs which included MET, AXL, EGFR was seen in 60-80% of cases; EGFR3, IGFR2, FGFR1, RET, PDGFR1, VEGFR2, PDGFR2 in 30-60% of cases; and EGFR4, FGFR3,VEGFR3 and ROS,IGFR1, EGFR1, FGFR2, VEGFR1 in 10-30% of cases. Immunoexpression of MET was seen in 89% of cases. A significant association was seen between MET mRNA and its protein expression. In all the cases MET gene expression was associated with worst overall survival (P = 0.03).There was a significant correlation of MET mRNA expression with RET, ROS, AXL, FGFR1, FGFR3, PDGFR1, IGFR1, VEGFR2, and EGFR3 genes. Association between MET gene and collective expression of RTKs was further evaluated by semi-supervised gene cluster analysis and Principal component analysis, which showed well-separated tumor clusters. MET gene overexpression could be a useful biomarker for identifying high risk orbital rhabdomyosarcoma patients. Well-separated tumor clusters confirmed the association between MET gene and collective expression of RTK genes. Therefore, the therapeutic potential of multi-kinase inhibitors targeting MET and the 9 other significant RTKs needs to be explored.

Gastric cancer (GC) is a prevalent malignant tumor and ranks as the second leading cause of death among cancer patients worldwide. Due to its hidden nature and difficulty in detection, GC has a high incidence and poor prognosis. Traditional treatment methods such as systemic chemotherapy, radiotherapy, and surgical resection are commonly used, but they often fail to achieve satisfactory curative effects, resulting in a very low 5-year survival rate for GC patients. Currently, targeted therapy and immunotherapy are prominent areas of research both domestically and internationally. These methods hold promise for the treatment of GC. This article focuses on the signaling pathways associated with the development of GC, as well as the recent advancements and applications of targeted therapy and immunotherapy. The aim is to provide fresh insights for the clinical treatment of GC.

The protein tyrosine kinase (PTK) produced by the BCR-ABL1 gene has generated significant interest in the development of inhibitors since the presence of punctual mutations causes resistance to currently approved drugs, mainly the T315I mutation has been the most difficult to address. In this work, derivatives of 1,6-dihydroazaazulenes are studied as possible inhibitors of this PTK in its wild form and the mutant T315I. The recognition of the ligands was explored through molecular docking, and the stability of the complexes and their evolution over time was studied using molecular dynamics (MD) simulations. Our results show that complexes are energetically stable and reside on the ATP binding site in all cases during the MD experiments. Interestingly, a few of our proposed ligands presented greater affinity for T315I, finding more favorable binding free energies (ΔG) than the reference drug axitinib. Furthermore, they may act as inhibitors for both isoforms. Our findings are promising because mutation of T315I does not prevent ligand recognition, as detailed in this work, which is very important to conduct further experimental research.Communicated by Ramaswamy H. Sarma.

To review the literature on the diagnosis and treatment of vestibular schwannoma.

Task force members were educated on knowledge synthesis methods, including electronic database search, review and selection of relevant citations, and critical appraisal of selected studies. Articles written in English or Portuguese on vestibular schwannoma were eligible for inclusion. The American College of Physicians' guideline grading system and the American Thyroid Association's guideline criteria were used for critical appraisal of evidence and recommendations for therapeutic interventions.

The topics were divided into 2 parts: (1) Diagnosis - audiologic, electrophysiologic tests, and imaging; (2) Treatment - wait and scan protocols, surgery, radiosurgery/radiotherapy, and systemic therapy.

Decision making in VS treatment has become more challenging. MRI can diagnose increasingly smaller tumors, which has disastrous consequences for the patients and their families. It is important to develop an individualized approach for each case, which highly depends on the experience of each surgical team.

Acute lung injury (ALI) is an acute inflammatory respiratory disease. The interaction between growth arrest-specific 6 (Gas6) and tyrosine kinases of the Tyro3, Axl, Mer (TAM) family plays an important role in a variety of physiological and pathological processes, including inflammation. In this study, we mainly clarified the mechanism of the Gas6/TAM signal pathway in lipopolysaccharide (LPS)-induced pulmonary epithelial cells (BEAS-2B cells) injury.

We cultured BEAS-2B cells in vitro and established a LPS-induced BEAS-2B cells injury model. Then, the siRNA sequence (siGas6-2) was transfected into cells. The expression of Gas6/TAM was measured based on quantitative reverse transcription polymerase chain reaction (qRT-RCR) and western blot (WB). Cell proliferation and apoptosis were measured by cell counting Kit-8 (CCK-8) and flow cytometry. The expression of pro-inflammatory factors was measured by qRT-RCR and WB.

Our study showed that when the 40 μg/mL LPS-induced BEAS-2B cells injury model was established, cell viability was significantly reduced, but the Gas6/TAM signal pathway was activated. When transfection with siGas6-2, low expression of Gas6 directly reduced the expression of downstream TAM receptors. Furthermore, the inhibition of the Gas6/TAM signal pathway significantly reduced the occurrence of cell apoptosis and the expression of inflammatory factors, and promoted cell proliferation.

Our research indicated that Gas6/TAM played an important role in cell proliferation, apoptosis, and inflammatory response in the LPS-induced BEAS-2B cells injury, and Gas6/TAM may be a new target in the treatment of ALI in the future.

Phosphoinositide 3-kinases (PI3Ks) generate lipids that control multitudinous intracellular cell signaling events which participate in cell survival and proliferation. In addition, PI3K signaling also contributes to metabolism, immunity, angiogenesis and cardiovascular homeostasis, and many diseases. The diverse actions of PI3K stem from the existence of their various isoforms and a variety of protein effectors. Hence, PI3K isoform-specific inhibitors have already achieved a wonderful effect on treating cancer. Herein, we summarize the molecular mechanism of PI3K inhibitors in preventing the permeability of vessels and neovascularization. Additionally, we briefly illustrate how PI3K signaling modulates blood vessel growth and discuss the different roles that PI3K isoforms play in angiogenesis.