Mitotic kinesins: prospects for antimitotic drug discovery.
Kinesins, mechanochemical enzymes that utilize the energy of ATP to translocate along or destabilize microtubules, are essential for accurate completion of cell division. Recently, small moleculer inhibitors of one kinesin, kinesin spindle protein (KSP/Eg5/kinesin5), have been shown to be efficacious in pre-clinical studies, with one quinazolinone-based inhibitor advancing to Phase II clinical trials as a potential anticancer chemotherapeutic agent. This highlights the potential of KSP and other mitotic kinesins as targets for chemotherapeutic intervention. Ten other kinesins have been shown to play essential roles in cell division and thus may provide additional therapeutic opportunities. In this review, the biological roles of these proteins are described with emphasis on their importance to cell proliferation. In addition, kinesin motor domain structure and mechanism are described with particular attention given to the conformational changes that offer opportunities for chemical inhibition. Finally, a current list of KSP inhibitor classes is described in the context of their potential as clinical leads.
Bergnes
Gustave
G
Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, CA 94080, USA. gbergnes@cytokinetics.com
Brejc
Katjusa
K
Belmont
Lisa
L
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008938:Mitosis / Q000502:physiology*; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D016547:Kinesins