Dual inhibition of Kif15 by oxindole and quinazolinedione chemical probes

Megan E. Dumas, Geng Yuan Chen, Nicole D. Kendrick, George Xu, Scott D. Larsen, Somnath Jana, Alex G. Waterson, Joshua A. Bauer, William Hancock, Gary A. Sulikowski, Ryoma Ohi

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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.

Original languageEnglish (US)
Pages (from-to)148-154
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number2
DOIs
StatePublished - Jan 15 2019

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Dumas, M. E., Chen, G. Y., Kendrick, N. D., Xu, G., Larsen, S. D., Jana, S., Waterson, A. G., Bauer, J. A., Hancock, W., Sulikowski, G. A., & Ohi, R. (2019). Dual inhibition of Kif15 by oxindole and quinazolinedione chemical probes. Bioorganic and Medicinal Chemistry Letters, 29(2), 148-154. https://doi.org/10.1016/j.bmcl.2018.12.008