Discovery and biochemical characterization of selective ATP competitive inhibitors of the human mitotic kinesin KSP |
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Authors: | Rickert Keith W Schaber Michael Torrent Maricel Neilson Lou Anne Tasber Edward S Garbaccio Robert Coleman Paul J Harvey Diane Zhang Yun Yang Yi Marshall Gary Lee Ling Walsh Eileen S Hamilton Kelly Buser Carolyn A |
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Affiliation: | a Department of Cancer Research, Merck Research Laboratories, P.O. Box 4, West Point, PA 19486, USA b Department of Molecular Systems, Merck Research Laboratories, P.O. Box 4, West Point, PA 19486, USA c Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, West Point, PA 19486, USA |
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Abstract: | The kinesin spindle protein (KSP, also known as Eg5) is essential for the proper separation of spindle poles during mitosis, and inhibition results in mitotic arrest and the formation of characteristic monoaster spindles. Several distinct classes of KSP inhibitors have been described previously in the public and patent literature. However, most appear to share a common induced-fit allosteric binding site, suggesting a common mechanism of inhibition. In a high-throughput screen for inhibitors of KSP, a novel class of thiazole-containing inhibitors was identified. Unlike the previously described allosteric KSP inhibitors, the thiazoles described here show ATP competitive kinetic behavior, consistent with binding within the nucleotide binding pocket. Although they bind to a pocket that is highly conserved across kinesins, these molecules exhibit significant selectivity for KSP over other kinesins and other ATP-utilizing enzymes. Several of these compounds are active in cells and produce a phenotype similar to that observed with previously published allosteric inhibitors of KSP. |
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Keywords: | Kinesin Inhibitor KSP Nucleotide Motor |
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