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 O. Hancock, Gary A. Sulikowski, Ryoma Ohi

Research output: Contribution to journalArticle

1 Citation (Scopus)

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

Fingerprint

Quinazolinones
Kinesin
Microtubules
Spindle Apparatus
Chromosomes
Pharmaceutical Preparations
Centrosome
Phosphotransferases
Cells
Mitosis
Cell Division
Proteins
oxindole
Neoplasms

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., ... 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
Dumas, Megan E. ; Chen, Geng Yuan ; Kendrick, Nicole D. ; Xu, George ; Larsen, Scott D. ; Jana, Somnath ; Waterson, Alex G. ; Bauer, Joshua A. ; Hancock, William O. ; Sulikowski, Gary A. ; Ohi, Ryoma. / Dual inhibition of Kif15 by oxindole and quinazolinedione chemical probes. In: Bioorganic and Medicinal Chemistry Letters. 2019 ; Vol. 29, No. 2. pp. 148-154.
@article{82bc4ed4f8424d04ab4ddea1608f68b0,
title = "Dual inhibition of Kif15 by oxindole and quinazolinedione chemical probes",
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.",
author = "Dumas, {Megan E.} and Chen, {Geng Yuan} and Kendrick, {Nicole D.} and George Xu and Larsen, {Scott D.} and Somnath Jana and Waterson, {Alex G.} and Bauer, {Joshua A.} and Hancock, {William O.} and Sulikowski, {Gary A.} and Ryoma Ohi",
year = "2019",
month = "1",
day = "15",
doi = "10.1016/j.bmcl.2018.12.008",
language = "English (US)",
volume = "29",
pages = "148--154",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "2",

}

Dumas, ME, Chen, GY, Kendrick, ND, Xu, G, Larsen, SD, Jana, S, Waterson, AG, Bauer, JA, Hancock, WO, Sulikowski, GA & Ohi, R 2019, 'Dual inhibition of Kif15 by oxindole and quinazolinedione chemical probes', Bioorganic and Medicinal Chemistry Letters, vol. 29, no. 2, pp. 148-154. https://doi.org/10.1016/j.bmcl.2018.12.008

Dual inhibition of Kif15 by oxindole and quinazolinedione chemical probes. / Dumas, Megan E.; Chen, Geng Yuan; Kendrick, Nicole D.; Xu, George; Larsen, Scott D.; Jana, Somnath; Waterson, Alex G.; Bauer, Joshua A.; Hancock, William O.; Sulikowski, Gary A.; Ohi, Ryoma.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 2, 15.01.2019, p. 148-154.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dual inhibition of Kif15 by oxindole and quinazolinedione chemical probes

AU - Dumas, Megan E.

AU - Chen, Geng Yuan

AU - Kendrick, Nicole D.

AU - Xu, George

AU - Larsen, Scott D.

AU - Jana, Somnath

AU - Waterson, Alex G.

AU - Bauer, Joshua A.

AU - Hancock, William O.

AU - Sulikowski, Gary A.

AU - Ohi, Ryoma

PY - 2019/1/15

Y1 - 2019/1/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85057587454&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057587454&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2018.12.008

DO - 10.1016/j.bmcl.2018.12.008

M3 - Article

C2 - 30528696

AN - SCOPUS:85057587454

VL - 29

SP - 148

EP - 154

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 2

ER -