title: Antitumor activity of a kinesin inhibitor.
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 Ki 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.
authors.affiliation: Cytokinetics, Inc., South San Francisco, California 94080, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Sakowicz
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Finer
authors.forename: Christophe
authors.initials: C
authors.lastname: Beraud
authors.forename: Anne
authors.initials: A
authors.lastname: Crompton
authors.forename: Evan
authors.initials: E
authors.lastname: Lewis
authors.forename: Alex
authors.initials: A
authors.lastname: Fritsch
authors.forename: Yan
authors.initials: Y
authors.lastname: Lee
authors.forename: John
authors.initials: J
authors.lastname: Mak
authors.forename: Robert
authors.initials: R
authors.lastname: Moody
authors.forename: Rebecca
authors.initials: R
authors.lastname: Turincio
authors.forename: John C
authors.initials: JC
authors.lastname: Chabala
authors.forename: Paul
authors.initials: P
authors.lastname: Gonzales
authors.forename: Stephanie
authors.initials: S
authors.lastname: Roth
authors.forename: Steve
authors.initials: S
authors.lastname: Weitman
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Wood
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011743:Pyrimidines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C487201:CK0106023; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D000251:Adenosine Triphosphatases; D016547:Kinesins