IC50: 4 nM
PRT-060318 is a novel Syk inhibitor.
Heparin-induced thrombocytopenia is a heparin therapy complication in which IgG antibodies against the platelet factor 4-heparin complex activate platelets. The FcγRIIA clustering initiates signaling cascades involving tyrosine kinases, such as spleen tyrosine kinase (Syk).
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].
Clinical trial: Up to now, PRT-060318 is still in the preclinical development stage.
Reference:
[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.