Orally active, highly potent and selective Syk inhibitor with in vivo efficacy in animal models of thrombosis and B-cell acute lymphoblastic leukemia (B-ALL).
PRT-060318 (PRT318; P142-76) is a highly potent and selective Syk inhibitor (IC50 = 4 nM; much reduced potency against 138 other kinases) that blocks BCR-dependent signaling in chronic lymphocytic leukemia (CCL) cultures (2-3 μM) and specifically inhibits platelets activation via ITAM receptor complex GPVI/FcRγ, but not P2Y1/12 or PAR1, stimulation (IC50 = 2.5 μM; aggregation by 8 ng/mL convulxin). PRT318 demonstrates in vivo efficacy in animal models of thrombosis (30 mg/kg mouse bis p.o.; 5.1675 mg/3.1 mL/kg/rabbit/15 min then 7.33 mg/4.4 mL/kg/h i.v.; 8.90 mg/mL/kg pig/h i.v.) and B-cell acute lymphoblastic leukemia (30 mg /kg bis p.o.; human B-ALL xenograft mice).
International journal of molecular sciences, 18(6) (2017-06-10)
The binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein 1b-IX (GP1b-IX) leads to activation of platelets. GP1b was shown to signal via the FcRγ-ITAM (Fc Receptor γ-Immunoreceptor tyrosine-based activation motif) pathway, activating spleen tyrosine kinase (Syk) and
Glycoprotein VI, a major platelet activation receptor for collagen and fibrin, is considered a particularly promising, safe antithrombotic target. In this study, we show that human glycoprotein VI signals upon platelet adhesion to fibrinogen. Full spreading of human platelets on
Gram-negative Escherichia coli cause diseases such as sepsis and hemolytic uremic syndrome in which thrombotic disorders can be found. Direct platelet-bacterium interactions might contribute to some of these conditions; however, mechanisms of human platelet activation by E. coli leading to
Heparin-induced thrombocytopenia (HIT) is a major cause of morbidity and mortality resulting from the associated thrombosis. Extensive studies using our transgenic mouse model of HIT have shown that antibodies reactive with heparin-platelet factor 4 complexes lead to FcγRIIA-mediated platelet activation
Syk is a protein tyrosine kinase that couples B-cell receptor (BCR) activation with downstream signaling pathways, affecting cell survival and proliferation. Moreover, Syk is involved in BCR-independent functions, such as B-cell migration and adhesion. In chronic lymphocytic leukemia (CLL), Syk
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