Centromere-associated protein-E (CENP-E) is a kinetochore-associated mitotic kinesin that acts as a kinetochore microtubule receptor responsible for silencing mitotic checkpoint signal transduction. GSK923295 is a small allosteric inhibitor of CENP-E kinesin motor ATPase activity with a Ki value of 3.2 nM. GSK923295 at 20 μM resulted in quantitative recovery of CENP-E motor domain with the microtubule pellet, and dramatically slowed down the release rate of inorganic phosphate (Pi) from CENP-E. Continuous exposure of GSK923295 for 72h showed growth inhibitory activity (GI50 value) ranging from 12 nM to more than 10000 nM with an average GI50 of 253 nM and a median GI50 of 32 nM in 237 tumor cell lines[3]. In mice bearing colon tumor xenografts, 24h after a single injection of 125 mg/kg GSK923295 increased the appearance of mitotic figures and scattered apoptotic bodies in tumors. Compared to vehicle-treated mice, GSK923295 administration (31.1 – 125 mg/kg) also dose-dependently increased the ratio of 4n to 2n nuclei in dispersed tumor tissues of colon tumor xenografts. Among five xenografts that received two-week consecutive treatment of GSK923295 (125 mg/kg, three daily doses), one showed a complete tumor regression and four showed had partial tumor regressions[3].
作用机制
GSK923295 is an organic allosteric inhibitor of CENP-E microtubule-stimulated ATPase activity that inhibits the release of inorganic phosphate (Pi) and stabilizes CENP-E motor domain interaction with microtubules[3].
GSK-923295 动物研究
Dose
Mice: 62.5 mg/kg[3] (i.p., 3 days on 4 days off for 2 weeks), 125 mg/kg[4] (i.p.)
United States, California
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GSK Investigational Site
Duarte, California, United States, 91010
United States, Michigan
GSK Investigational Site
Detroit, Michigan, United States, 48201
United States, Wisconsin
GSK Investigational Site
Madison, Wisconsin, United States, 53792-5666 收起 <<
United States, California
... 展开 >>
GSK Investigational Site
Duarte, California, United States, 91010
United States, Michigan
GSK Investigational Site
Detroit, Michigan, United States, 48201
United States, Wisconsin
GSK Investigational Site
Madison, Wisconsin, United States, 53792-5666 收起 <<
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