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

doi:10.1016/j.bmcl.2018.12.008

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.

Authors

Affiliations

¹ Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, United States.
² Department of Biomedical Engineering, Pennsylvania State University, State College, PA, United States.
³ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, United States.
⁴ Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States.
⁵ Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, United States.
⁶ Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, United States; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, United States.
⁷ Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, United States.
⁸ Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States.
⁹ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, United States; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address: oryoma@umich.edu.

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
Kinesins / antagonists & inhibitors*
Kinesins / 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
Kinesins

Abstract

Publication types

MeSH terms

Substances

Grants and funding