Dual inhibition of Kif15 by oxindole and quinazolinedione chemical probes

Bioorg Med Chem Lett. 2019 Jan 15;29(2):148-154. doi: 10.1016/j.bmcl.2018.12.008. Epub 2018 Dec 4.

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.

Keywords: Eg5; Kif15; Kinesin; Mitosis; Oxindole.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Kinesin / antagonists & inhibitors*
  • Kinesin / metabolism
  • Molecular Probes / chemical synthesis
  • Molecular Probes / chemistry
  • Molecular Probes / pharmacology*
  • Molecular Structure
  • Oxindoles / chemical synthesis
  • Oxindoles / chemistry
  • Oxindoles / pharmacology*
  • Quinazolinones / chemical synthesis
  • Quinazolinones / chemistry
  • Quinazolinones / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • KIF15 protein, human
  • Molecular Probes
  • Oxindoles
  • Quinazolinones
  • Kinesin