GSK923295 Kinesin inhibitor

GSK923295 is the first potent and selective inhibitor of the mitotic kinesin centromere-associated protein-E (CENP-E). [1][2] This compound is uncompetitive with both ATP and microtubules (MT), inhibiting CENP-E MT-stimulated ATPase activity with a K_i of 3.2 nM, highly selective over other kinesins. It inhibits release of inorganic phosphate and stabilises CENP-E motor domain interaction with microtubules, reduces the rate of ATP-promoted dissociation of CENP-E from MT (k_{off, MT}) by more than 50-fold. This chemical causes failure of metaphase chromosome alignment and induces mitotic arrest. It is a potent inhibitor of tumour cell growth, with an average GI50 of 253 nM and a median GI50 of 32 nM for 237 tumour cell lines. [1] This compound inhibits tumour cell growth more effectively when mitogen-activated protein kinase (MEK/ERK) signalling is also inhibited. [4]

GSK923295 produces clear increases in the abundance of mitotic figures and scattered apoptotic bodies in tumours. This compound causes a dose-dependent increase in the ratio of 4n to 2n nuclei. It exhibits robust, dose-dependent antitumour activity against Colo205 xenografts, including partial and complete regressions at the 125 mg/kg dose.[1] It demonstrates significant antitumour activity against solid tumour models, inducing CRs in Ewing sarcoma, rhabdoid, and rhabdomyosarcoma xenografts, may be a valuable therapeutic target in paediatric cancer. [3]