PRT-060318

Description

PRT060318 is a potent and selective inhibitor of spleen tyrosine kinase (Syk; IC₅₀ = 4 nM). It is selective, inhibiting 92% of Syk activity, while other kinases retain >70% activity, at a concentration of 50 nM in a panel of 270 kinases. PRT060318 inhibits convulxin-induced aggregation of human platelet-rich plasma (IC₅₀ = 2.5 μM) in vitro and prevents thrombosis in a transgenic mouse model of heparin-induced thrombocytopenia. It induces chronic lymphocytic leukemia (CLL) B cell apoptosis and inhibits the secretion of chemokines CCL3, CCL4, and CXCL13. PRT060318 also inhibits CLL B cell chemotaxis and pseudoemperipolesis.

The Uses of PRT-060318

PRT 060318 is a novel selective inhibitor of the tyrosine kinase Syk. PRT 060318 may be used in Heparin-Induced Thrombocytopenia (HIT) treatment. HIT is a major cause of morbidity and mortality.

in vitro

prt-060318 was identified as a potent inhibitor of purified syk kinase. syk kinase was inhibited by 92%, while the activities all other kinases retained more than 70% when prt-060318 were evaluated at a concentration of 50 nm in a broad panel of kinase enzyme assays. in addition, prt-060318 could dose-responsively inhibited convulxin-induced human prp aggregation. moreover, it was found that prt-060318 was able to dose-responsively inhibit the increases in intracellular calcium in convulxin-treated platelets [1].

in vivo

animal study showed that in contrast to vehicle-treated mice developed the expected thrombocytopenia, prt-060318-treated mice had no significant change in platelet counts after injection of heparin. moreover, the nadir platelet counts of prt-060318-treated mice were found to be significantly higher than control mice. the prt-060318-treated mice showed no bleeding diathesis or other adverse effects. in addition, prt-060318 treatment in crush thrombosis model resulted in significant inhibition of platelet deposition without changing bleeding time [1].

References

[1] reilly mp,sinha u,andré p,taylor sm,pak y,deguzman fr,nanda n,pandey a,stolla m,bergmeier w,mckenzie se. prt-060318, a novel syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model. blood.2011 feb 17;117(7):2241-6.