Antitumor activity of an allosteric inhibitor of centromere-associated protein-E

• DOI: 10.1073/pnas.0915068107
• Publication Date: 2010-02-19T03:15:23Z
• Authors: Kenneth W. Wood; Latesh Lad; Lusong Luo; Xiangping Qian; Steven D. Knight; Neysa Nevins; Katjusa Brejc; David Sutton; Aidan G. Gilmartin; Penelope R. Chua; Radhika Desai; Stephen P. Schauer; Dean E. McNulty; Roland S. Annan; Lisa D. Belmont; Carlos Garcia; Yan Lee; Melody A. Diamond; Leo F. Faucette; Michele Giardiniere; ShuYun Zhang; Chiu-Mei Sun; Justin D. Vidal; Serge Lichtsteiner; William D. Cornwell; Joel D. Greshock; Richard F. Wooster; Jeffrey T. Finer; Robert A. Copeland; Pearl S. Huang; David J. Morgans; Dashyant Dhanak; Gustave Bergnes; Roman Sakowicz; Jeffrey R. Jackson
• Keywords: Models, Molecular; 0301 basic medicine; Binding Sites; Molecular Structure; Chromosomal Proteins, Non-Histone; Kinesins; Mitosis; Antineoplastic Agents; Sarcosine; In Vitro Techniques; Bridged Bicyclo Compounds, Heterocyclic; Microtubules; Xenograft Model Antitumor Assays; Mice; 03 medical and health sciences; Dogs; Cell Line, Tumor; Animals; Humans; Drug Screening Assays, Antitumor; Allosteric Site

Centromere-associated protein-E (CENP-E) is a kinetochore-associated mitotic kinesin that is thought to function as the key receptor responsible for mitotic checkpoint signal transduction after interaction with spindle microtubules. We have identified GSK923295, an allosteric inhibitor of CENP-E kinesin motor ATPase activity, and mapped the inhibitor binding site to a region similar to that bound by loop-5 inhibitors of the kinesin KSP/Eg5. Unlike these KSP inhibitors, which block release of ADP and destabilize motor-microtubule interaction, GSK923295 inhibited release of inorganic phosphate and stabilized CENP-E motor domain interaction with microtubules. Inhibition of CENP-E motor activity in cultured cells and tumor xenografts caused failure of metaphase chromosome alignment and induced mitotic arrest, indicating that tight binding of CENP-E to microtubules is insufficient to satisfy the mitotic checkpoint. Consistent with genetic studies in mice suggesting that decreased CENP-E function can have a tumor-suppressive effect, inhibition of CENP-E induced tumor cell apoptosis and tumor regression.