Abstract
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.
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Acknowledgements
The authors would like to acknowledge N. Monaco for her help with the proliferation assays and cell culture.
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All authors are employed by GlaxoSmithKline or Cytokinetics for biomedical research. P.S.H. was employed by GlaxoSmithKline but is now at Merck and Co.
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Luo, L., Parrish, C., Nevins, N. et al. ATP-competitive inhibitors of the mitotic kinesin KSP that function via an allosteric mechanism. Nat Chem Biol 3, 722–726 (2007). https://doi.org/10.1038/nchembio.2007.34
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DOI: https://doi.org/10.1038/nchembio.2007.34
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