Letter abstract
Nature Chemical Biology 3, 722 - 726 (2007)
Published online: 7 October 2007 | doi:10.1038/nchembio.2007.34
ATP-competitive inhibitors of the mitotic kinesin KSP that function via an allosteric mechanism
Lusong Luo1, Cynthia A Parrish2, Neysa Nevins3, Dean E McNulty3, Amita M Chaudhari2, Jeffery D Carson1, Valery Sudakin4, Antony N Shaw2, Ruth Lehr5, Huizhen Zhao5, Sharon Sweitzer5, Latesh Lad6, Kenneth W Wood6, Roman Sakowicz6, Roland S Annan3, Pearl S Huang4,7, Jeffrey R Jackson4, Dashyant Dhanak2, Robert A Copeland1,4 & Kurt R Auger4
The mitotic kinesin KSP (kinesin spindle protein, or Eg5) has an essential role in centrosome separation and formation of the bipolar mitotic spindle1, 2. Its exclusive involvement in the mitotic spindle of proliferating cells presents an opportunity for developing new anticancer agents with reduced side effects relative to antimitotics that target tubulin3, 4, 5. Ispinesib (1) is an allosteric small-molecule KSP inhibitor in phase 2 clinical trials. Mutations that attenuate ispinesib binding to KSP have been identified, which highlights the need for inhibitors that target different binding sites. We describe a new class of selective KSP inhibitors that are active against ispinesib-resistant forms of KSP. These ATP-competitive KSP inhibitors do not bind in the nucleotide binding pocket. Cumulative data from generation of resistant cells, site-directed mutagenesis and photo-affinity labeling suggest that they compete with ATP binding via a novel allosteric mechanism.
- Department of Enzymology and Mechanistic Pharmacology, Oncology CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
- Department of Medicinal Chemistry, Oncology CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
- Department of Computational, Analytical and Structural Sciences, Molecular Discovery Research, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
- Department of Biology, Oncology CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
- Biological Reagents and Assay Development, Molecular Discovery Research, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, USA.
- Present address: Merck and Co., Oncology Franchise, 770 Sumneytown Pike, West Point, Pennsylvania 19486, USA.
Correspondence to: Lusong Luo1 e-mail: lusong.luo@gsk.com
Correspondence to: Cynthia A Parrish2 e-mail: cynthia.a.parrish@gsk.com
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