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

RIP1:29 nM

GSK 963在体外相对于Nec-1显示出更高的效能，此增强效力亦在TNF+zVAD诱导的无菌性休克模型中体现为更高的疗效。以2 mg/kg的剂量，GSK 963能够完全抑制TNF+zVAD引起的温度下降，这一表型与最近描述的RIP1激酶失活敲入小鼠的表型相符。在这个急性模型中，GSK 963不同剂量对温度下降的抑制水平与基于GSK 963药代动力学特性和体外效力模型预测的疗效相一致。

GSK 963在啮齿类和人类细胞中高效阻断坏死性细胞死亡，其IC50值分别为1 nM和4 nM。相比之下，不活跃的类似物GSK 962在这些测试中的效力至少低1000倍。

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).