Antitumor activity of a kinesin inhibitor.
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.
Sakowicz
Roman
R
Cytokinetics, Inc., South San Francisco, California 94080, USA.
Finer
Jeffrey T
JT
Beraud
Christophe
C
Crompton
Anne
A
Lewis
Evan
E
Fritsch
Alex
A
Lee
Yan
Y
Mak
John
J
Moody
Robert
R
Turincio
Rebecca
R
Chabala
John C
JC
Gonzales
Paul
P
Roth
Stephanie
S
Weitman
Steve
S
Wood
Kenneth W
KW
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
D000970:Antineoplastic Agents; C487201:CK0106023; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D000251:Adenosine Triphosphatases; D016547:Kinesins