Dual inhibition of Kif15 by oxindole and quinazolinedione chemical probes. Issue 2 (15th January 2019)

• Record Type: Journal Article
• Authors: Dumas, Megan E.; Chen, Geng-Yuan; Kendrick, Nicole D.; Xu, George; Larsen, Scott D.; Jana, Somnath; Waterson, Alex G.; Bauer, Joshua A.; Hancock, William; Sulikowski, Gary A.; Ohi, Ryoma
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 2(2019)
• Page Start: 148
• Page End: 154
• Publication Date: 2019-01-15
• Subjects: Kinesin -- Mitosis -- Oxindole -- Kif15 -- Eg5; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.12.008
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The mitotic spindle is a microtubule-based machine that segregates a replicated set of chromosomes during cell division. Many cancer drugs alter or disrupt the microtubules that form the mitotic spindle. Microtubule-dependent molecular motors that function during mitosis are logical alternative mitotic targets for drug development. Eg5 (Kinesin-5) and Kif15 (Kinesin-12), in particular, are an attractive pair of motor proteins, as they work in concert to drive centrosome separation and promote spindle bipolarity. Furthermore, we hypothesize that the clinical failure of Eg5 inhibitors may be (in part) due to compensation by Kif15. In order to test this idea, we screened a small library of kinase inhibitors and identified GW108X, an oxindole that inhibits Kif15 in vitro . We show that GW108X has a distinct mechanism of action compared with a commercially available Kif15 inhibitor, Kif15-IN-1 and may serve as a lead with which to further develop Kif15 inhibitors as clinically relevant agents.