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PMID: 24900171 Published · epublish English

Discovery of the First Potent and Selective Inhibitor of Centromere-Associated Protein E: GSK923295.

ACS medicinal chemistry letters ·Vol. 1 ·No. 1 ·2014-06-05

Qian Xiangping, McDonald Andrew, Zhou Han-Jie, Adams Nicholas D, Parrish Cynthia A, Duffy Kevin J, Fitch Duke M, Tedesco Rosanna, Ashcraft Luke W, Yao Bing, Jiang Hong, Huang Jennifer K, Marin Melchor V, Aroyan Carrie E, Wang Jianchao, Ahmed Seyed, Burgess Joelle L, Chaudhari Amita M, Donatelli Carla A, Darcy Michael G, Ridgers Lance H, Newlander Ken A, Schmidt Stanley J, Chai Deping, Colón Mariela, Zimmerman Michael N, Lad Latesh, Sakowicz Roman, Schauer Stephen, Belmont Lisa, Baliga Ramesh, Pierce Daniel W, Finer Jeffrey T, Wang Zhengping, Morgan Bradley P, Morgans David J, Auger Kurt R, Sung Chiu-Mei, Carson Jeff D, Luo Lusong, Hugger Erin D, Copeland Robert A, Sutton David, Elliott John D, Jackson Jeffrey R, Wood Kenneth W, Dhanak Dashyant, Bergnes Gustave, Knight Steven D

Abstract

Inhibition of mitotic kinesins represents a novel approach for the discovery of a new generation of anti-mitotic cancer chemotherapeutics. We report here the discovery of the first potent and selective inhibitor of centromere-associated protein E (CENP-E) 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide (GSK923295; 1), starting from a high-throughput screening hit, 3-chloro-4-isopropoxybenzoic acid 2. Compound 1 has demonstrated broad antitumor activity in vivo and is currently in human clinical trials.

Keywords
CENP-E GSK923295 inhibitor mitotic kinesin
Article Info
Journal
ACS medicinal chemistry letters
Abbr.
ACS Med Chem Lett
Published
2014-06-05
Indexed
2014-06-05
Updated
2014-06-09
Language
English
Country/Region
United States
NLM ID
101521073
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