For research use only. Not Intended for Therapeutic Use!
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GSK923295 is a first-in-class, specific allosteric inhibitor of CENP-E kinesin motor ATPase with Ki of 3.2 nM, and less potent to mutant I182 and T183.
IC50 Value: 3.2 nM(Ki)
in vitro: GSK923295 is uncompetitive with both ATP and microtubules (MT), inhibiting CENP-E MT-stimulated ATPase activity with a Ki of 3.2 nM, highly selective over other kinesins. GSK923295 inhibits release of inorganic phosphate and stabilizes CENP-E motor domain interaction with microtubules, reduces the rate of ATP-promoted dissociation of CENP-E from MT (koff, MT) by more than 50-fold. GSK923295 causes failure of metaphase chromosome alignment and induces mitotic arrest. GSK923295 is a potent inhibitor of tumor cell growth, with an average GI50 of 253 nM and a median GI50 of 32 nM for 237 tumor cell lines. GSK923295 inhibits tumor cell growth more effectively when mitogen-activated protein kinase (MEK/ERK) signaling is also inhibited.
in vivo: GSK923295 produces clear increases in the abundance of mitotic figures and scattered apoptotic bodies in tumors. GSK923295 causes a dose-dependent increase in the ratio of 4n to 2n nuclei. GSK923295 exhibits robust, dose-dependent antitumor activity against Colo205 xenografts, including partial and complete regressions at the 125 mg/kg dose. GSK923295 demonstrates significant antitumor activity against solid tumor models, inducing CRs in Ewing sarcoma, rhabdoid, and rhabdomyosarcoma xenografts, may be a valuable therapeutic target in pediatric cancer.
. Xiangping Qian et al Discovery of the First Potent and Selective Inhibitor of Centromere-Associated Protein E: GSK923295. ACS Med. Chem. Lett., 2010, 1 (1), pp 30-34
. Chung V, Heath EI, Schelman WR, Johnson BM, Kirby LC, Lynch KM, Botbyl JD, Lampkin TA, Holen KD.First-time-in-human study of GSK923295, a novel antimitotic inhibitor of centromere-associated protein E (CENP-E), in patients with refractory cancer.Cancer Chemother Pharmacol. 2012 Mar;69(3):733-41. Epub 2011 Oct 22.
. Mayes PA, Degenhardt YY, Wood A, Toporovskya Y, Diskin SJ, Haglund E, Moy C, Wooster R, Maris JM.Mitogen-activated protein kinase (MEK/ERK) inhibition sensitizes cancer cells to centromere-associated protein E (CENP-E) inhibition.Int J Cancer. 2012 Sep 5.
. Balamuth NJ, Wood A, Wang Q, Jagannathan J, Mayes P, Zhang Z, Chen Z, Rappaport E, Courtright J, Pawel B, Weber B, Wooster R, Sekyere EO, Marshall GM, Maris JM.Serial transcriptome analysis and cross-species integration identifies centromere-associated protein E as a novel neuroblastoma target.Cancer Res. 2010 Apr 1;70(7):2749-58. Epub 2010 Mar 16.
. Wood KW, Lad L, Luo L, Qian X, Knight SD, Nevins N, Brejc K, Sutton D, Gilmartin AG, Chua PR, Desai R, Schauer SP, McNulty DE, Annan RS, Belmont LD, Garcia C, Lee Y, Diamond MA, Faucette LF, Giardiniere M, Zhang S, Sun CM, Vidal JD, Lichtsteiner S, Cornwell WD, Greshock JD, Wooster RF, Finer JT, Copeland RA, Huang PS, Morgans DJ Jr, Dhanak D, Bergnes G, Sakowicz R, Jackson JR.Antitumor activity of an allosteric inhibitor of centromere-associated protein-E.Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5839-44. Epub 2010 Feb 18.