GSK-923295

GSK923295 is a specific inhibitor of CENP-E kinesin motor with IC50 value of 3.2 nM [1].

Centromere-associated protein E (CENP-E) is a mitotic kinesin, which is the connect of mitosis process with the mitotic checkpoint signaling. It Interacts with spindle microtubules and contribute to the chromosome alignment, and thus it regulates the cell-cycle transition from metaphase to anaphase.

When asynchronous cultured cells were exposed to GSK923295, the penetrant cell-cycle delay in mitosis was observed, which accompanied with morphological changes similar to RNAi-mediated knockdown of CENP-E mRNA. It indicated a significant inhibition of CENP-E by GSK923295. In the presence of GSK9232195, CENP-E microtubule (MT)-stimulated ATPase showed a dramatic slowing of release of ADP and Pi, where the ATP-bound form was stabilized and the activity of CENP-E was inhibited. This observation suggested GSK923295 inhibited CENP-E via the suppression of MT-stimulated ATPase [1].

In mouse model, mice bearing xenografts of the Colo205 colon tumor cell line were administered with GSK923295 of 125 mg/kg. The result showed GSK923295-induced cell-cycle changes of tumor cells and increased scattered apoptosis body. Additionally, long-term study via measuring tumor volume revealed significant antitumor activity of GSK923295, in a manner of dose-dependent [1].

Reference:
[1] Wood K W et al. , Antitumor activity of an allosteric inhibitor of centromere-associated protein-E. 2010, 107 (13): 5839-5844.

Small Molecules Identified from a Quantitative Drug Combinational Screen Resensitize Cisplatin's Response in Drug-Resistant Ovarian Cancer Cells.[Pubmed:29982103]

Transl Oncol. 2018 Aug;11(4):1053-1064.

Drug resistance to chemotherapy occurs in many ovarian cancer patients resulting in failure of treatment. Exploration of drug resistance mechanisms and identification of new therapeutics that overcome the drug resistance can improve patient prognosis. Following a quantitative combination screen of 6060 approved drugs and bioactive compounds in a cisplatin-resistant A2780-cis ovarian cancer cell line, 38 active compounds with IC50s under 1 muM suppressed the growth of cisplatin-resistant ovarian cancer cells. Among these confirmed compounds, CUDC-101, OSU-03012, oligomycin A, VE-821, or Torin2 in a combination with cisplatin restored cisplatin's apoptotic response in the A2780-cis cells, while SR-3306, GSK-923295, SNX-5422, AT-13387, and PF-05212384 directly suppressed the growth of A2780-cis cells. One of the mechanisms for overcoming cisplatin resistance in these cells is mediated by the inhibition of epidermal growth factor receptor (EGFR), though not all the EGFR inhibitors are equally active. The increased levels of total EGFR and phosphorylated-EGFR (p-EGFR) in the A2780-cis cells were reduced after the combined treatment of cisplatin with EGFR inhibitors. In addition, a knockdown of EGFR mRNA reduced cisplatin resistance in the A2780-cis cells. Therefore, the top active compounds identified in this work can be studied further as potential treatments for cisplatin-resistant ovarian cancer. The quantitative combinational screening approach is a useful method for identifying effective compounds and drug combinations against drug-resistant cancer cells.

GSK-923295 is a special, allosteric inhibitor of centromere-associated protein-E (CENP-E) kinesin motor ATPase activity, with Ki of 3.2±0.2 nM and 1.6± 0.1 nM for human and canine, respectively.

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