Antitumor Activity of an Allosteric Inhibitor of Centromere-associated Protein-E

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Feb 20

PMID 20167803

Citations 128

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 Jr

Dashyant Dhanak

Gustave Bergnes

Roman Sakowicz

Jeffrey R Jackson

Affiliations

Soon will be listed here.

Abstract

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.

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