Antitumor Activity of a Kinesin Inhibitor

Roman Sakowicz, Jeffrey T. Finer, Christophe Beraud, Anne Crompton, Evan Lewis, Alex Fritsch, Yan Lee, John Mak, Robert Moody, Rebecca Turincio, John C. Chabala, Paul Gonzales, Stephanie Roth, Steve Weitman, Kenneth W. Wood

Research output: Contribution to journalArticlepeer-review

238 Scopus citations

Abstract

Several members of the kinesin family of microtubule motor proteins play essential roles in mitotic spindle function and are potential targets for the discovery of novel antimitotic cancer therapies. KSP, also known as HsEg5, is a kinesin that plays an essential role in formation of a bipolar mitotic spindle and is required for cell cycle progression through mitosis. We identified a potent inhibitor of KSP, CK0106023, which causes mitotic arrest and growth inhibition in several human tumor cell lines. Here we show that CK0106023 is an allosteric inhibitor of KSP motor domain ATPase with a K1 of 12 nM. Among five kinesins tested, CK0106023 was specific for KSP. In tumor-bearing mice, CK0106023 exhibited antitumor activity comparable to or exceeding that of paclitaxel and caused the formation of monopolar mitotic figures identical to those produced in cultured cells. KSP was most abundant in proliferating human tissues and was absent from cultured postmitotic neurons. These findings are the first to demonstrate the feasibility of targeting mitotic kinesins for the treatment of cancer.

Original languageEnglish (US)
Pages (from-to)3276-3280
Number of pages5
JournalCancer Research
Volume64
Issue number9
DOIs
StatePublished - May 1 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Antitumor Activity of a Kinesin Inhibitor'. Together they form a unique fingerprint.

Cite this