GSK963 (Racemate), a structurally distinct, potent and selective inhibitor of RIP1 kinase(IC50=29 nM).

RIP1:29 nM

The increased potency of GSK 963 relative to Nec-1 in vitro also translated into increased efficacy in the TNF+zVAD-induced model of sterile shock.?At a dose of 2 mg/kg, GSK 963 was able to completely inhibit temperature loss in response to TNF+zVAD, ?the phenotype of the recently described RIP1 kinase-dead knock-in mice.?The level of inhibition of temperature loss in this acute model at different doses of GSK 963 was in line with the predictions of efficacy based on modeling of the pharamacokinetic profile and in vitro potency of GSK 963.

GSK 963 efficiently blocked necroptosis in both murine and human cells with IC50 values of 1 nM and 4 nM, respectively, whereas the inactive analog GSK 962 was at least 1000-fold less potent in these assays.

GSK′963 was tested against 339 kinases using a P33-radiolabeled assay at Reaction Corp Biology. The compound was tested at a single dose in duplicate at 10?μM. Reactions were carried out at 10?μM ATP. Data are reported as % enzyme activity (relative to DMSO controls).