Copyright ©The Author(s) 2020.
World J Gastroenterol. Mar 14, 2020; 26(10): 1005-1019
Published online Mar 14, 2020. doi: 10.3748/wjg.v26.i10.1005
Table 1 Summary of pre-clinical and clinical studies using spleen tyrosine kinase inhibitors
CompoundMedical conditionDescription/effectRef.
Fostamatinib (R788)Ulcerative colitisSuppression of TNFα, T cells and neutrophils[106]
Rheumatoid arthritisReduced inflammation and tissue damage, suppressed clinical arthritis, pannus formation and synovitis[107,108]
Chronic lymphocytic leukemia and Non-Hodgkin lymphomaDisruption of BCR signaling inhibiting the proliferation and survival of malignant B cells[109,110]
Ischemia-reperfusion induced intestinal and lung damageImpaired release of pro-inflammatory and coagulation mediators, reduced neutrophils, macrophages and platelet accumulations[111]
GlomerulonephritisReduced proteinuria, glomerular macrophage and CD8 cells, MCP-1 and IL-1β, and renal injury[112]
Entospletinib (GS-9973)Chronic lymphocytic leukemiaDecreased inflammation and disruption of chemokine/cytokine circuits (BCR signaling)[113-115]
Diffuse large B-cell lymphomaDisruption of BCR signaling inhibiting the proliferation and survival of malignant B cells[116]
Cherubisme (craniofacial disorder)Ameliorates inflammation and bone destruction in the mouse model of cherubism[117]
Cerdulatinib (PRT062070)Diffuse large B-cell lymphomaDisruption of BCR signalling inhibiting the proliferation and survival of malignant B cells[118,119]
TAK-659Epstein-Barr virus-associated lymphomaInhibited tumour development and metastases[120]
Chronic lymphocytic leukemiaDecreased tumour survival, myeloid cell proliferation and metastasis[121]
R406 (tamatinib)Immunocomplexes mediated inflammationInhibits several critical modes of the inflammatory cascade[122]
Human plateletsInhibition of activation of CLEC-2 (C-type lectin 2, platelet receptor), and platelet activation[123]
Chronic lymphocytic leukemiaInhibition of constitutive and BCR-induced SYK activation, abrogation of CLL cell survival, migration, and paracrine signalling[124]
LeukemiaReduced tyrosine phosphorylation and c-Myc expression, blockade of tumorigenic cells proliferation transformed by oncogenes[125]
Megakaryocytic leukemiaInduced apoptosis, reduced cell proliferation and blockade of STAT5 signalling[126]
GlomerulonephritisDownregulated MCP-1 production from mesangial cells and macrophages[112]
PiceatannolOral squamous cell carcinomaInhibited tumour cell proliferation, induced of apoptosis, attenuated VEGF and MMP9 expression, and decreased metastases[127]
Table 2 Spleen tyrosine kinase inhibitors implicated in liver diseases
InhibitorMechanism of actionTherapeutic effectRef.
R406Blocking of Fc receptor signalling pathway, NF-κB signalling pathway and inflammasome activationReduced SYK expression and phosphorylation resulting in attenuated liver steatosis, inflammation and fibrosis in ASH and NASH murine models[20,44]
GS-9973Decreased expression of HSCs activation (CBP, MYB, MYC) and HSCs proliferation factors (MYC and CCND1)Inhibition of HSCs proliferation and HSC activation resulting in amelioration of fibrosis and hepatocarcinogenesis[28]
PRT062607 and piceatannolIncreased intra-tumoral p16, p53 and decreased expression of Bcl-xL and SMAD4. Decreased expression of genes regulating angiogenesis, apoptosis, cell cycle regulation and cellular senescence. Down-regulation of mTOR, IL-8 signalling and oxidative phosphorylationReduced HSCs differentiation and infiltration of inflammatory cells including T cells, B cells and myeloid cells, reduced oncogenic progression. Marked attenuation of toxin-induced liver fibrosis, associated hepatocellular injury, intra-hepatic inflammation and hepatocarcinogenesis[128]