title: Discovery of the First Potent and Selective Inhibitor of Centromere-Associated Protein E: GSK923295.
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.
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Xiangping
authors.initials: X
authors.lastname: Qian
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Andrew
authors.initials: A
authors.lastname: McDonald
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Han-Jie
authors.initials: HJ
authors.lastname: Zhou
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Adams
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Parrish
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Duffy
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Duke M
authors.initials: DM
authors.lastname: Fitch
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Tedesco
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Luke W
authors.initials: LW
authors.lastname: Ashcraft
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Huang
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Melchor V
authors.initials: MV
authors.lastname: Marin
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Carrie E
authors.initials: CE
authors.lastname: Aroyan
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Jianchao
authors.initials: J
authors.lastname: Wang
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Seyed
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Joelle L
authors.initials: JL
authors.lastname: Burgess
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Amita M
authors.initials: AM
authors.lastname: Chaudhari
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Carla A
authors.initials: CA
authors.lastname: Donatelli
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Darcy
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Lance H
authors.initials: LH
authors.lastname: Ridgers
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Ken A
authors.initials: KA
authors.lastname: Newlander
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Schmidt
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Deping
authors.initials: D
authors.lastname: Chai
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Mariela
authors.initials: M
authors.lastname: Colón
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Zimmerman
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Latesh
authors.initials: L
authors.lastname: Lad
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Roman
authors.initials: R
authors.lastname: Sakowicz
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Stephen
authors.initials: S
authors.lastname: Schauer
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Lisa
authors.initials: L
authors.lastname: Belmont
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Baliga
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Pierce
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Finer
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Morgan
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: David J
authors.initials: DJ
authors.lastname: Morgans
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Auger
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Chiu-Mei
authors.initials: CM
authors.lastname: Sung
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Jeff D
authors.initials: JD
authors.lastname: Carson
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Lusong
authors.initials: L
authors.lastname: Luo
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Erin D
authors.initials: ED
authors.lastname: Hugger
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: David
authors.initials: D
authors.lastname: Sutton
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: John D
authors.initials: JD
authors.lastname: Elliott
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jackson
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Wood
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Dashyant
authors.initials: D
authors.lastname: Dhanak
authors.affiliation: Cytokinetics, Inc., 280 E Grand Avenue, South San Francisco, California 94080.
authors.forename: Gustave
authors.initials: G
authors.lastname: Bergnes
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Knight
keywords: CENP-E; GSK923295; inhibitor; mitotic kinesin