ATP-competitive inhibitors of the mitotic kinesin KSP that function via an allosteric mechanism |
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Authors: | Luo Lusong Parrish Cynthia A Nevins Neysa McNulty Dean E Chaudhari Amita M Carson Jeffery D Sudakin Valery Shaw Antony N Lehr Ruth Zhao Huizhen Sweitzer Sharon Lad Latesh Wood Kenneth W Sakowicz Roman Annan Roland S Huang Pearl S Jackson Jeffrey R Dhanak Dashyant Copeland Robert A Auger Kurt R |
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Institution: | Department of Enzymology and Mechanistic Pharmacology, Oncology CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. lusong.luo@gsk.com |
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Abstract: | The mitotic kinesin KSP (kinesin spindle protein, or Eg5) has an essential role in centrosome separation and formation of the bipolar mitotic spindle. 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 tubulin. Ispinesib 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. |
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