Discovery and biochemical characterization of selective ATP competitive inhibitors of the human mitotic kinesin KSP

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 t...

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Bibliographic Details
Published in:Archives of biochemistry and biophysics 2008-01, Vol.469 (2), p.220-231
Main 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.
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - chemistry
Adenosine Triphosphate - metabolism
Allosteric Site
Binding, Competitive
Biochemistry - methods
Drug Design
Humans
Inhibitor
Kinesin
Kinesin - antagonists & inhibitors
Kinesin - chemistry
Kinesin - metabolism
KSP
Mitosis
Models, Biological
Models, Chemical
Motor
Nucleotide
Nucleotides - chemistry
Phenotype
Protein Binding
Thiazoles - pharmacology
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Summary: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.
ISSN:0003-9861
1096-0384
DOI:10.1016/j.abb.2007.10.016