ATP-competitive inhibitors of the mitotic kinesin KSP that function via an allosteric mechanism.

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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@article{Luo2007ATPcompetitiveIO, title={ATP-competitive inhibitors of the mitotic kinesin KSP that function via an allosteric mechanism.}, author={Lusong Luo and Cynthia A Parrish and Neysa Nevins and Dean E. McNulty and Amita M Chaudhari and Jeffery D Carson and Valery Sudakin and Antony N Shaw and Ruth Lehr and Huizhen Zhao and Sharon M. Sweitzer and Latesh Lad and K. W. Wood and Roman Sakowicz and Roland S. Annan and Pearl S. Huang and Jeffrey R. Jackson and Dashyant Dhanak and Robert A. Copeland and Kurt R. Auger}, journal={Nature chemical biology}, year={2007}, volume={3 11}, pages={722-6} }