title: Antitumor activity of an allosteric inhibitor of centromere-associated protein-E.
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.
authors.affiliation: Cytokinetics Inc, South San Francisco, CA 94080, USA. kwood@cytokinetics.com
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Wood
authors.forename: Latesh
authors.initials: L
authors.lastname: Lad
authors.forename: Lusong
authors.initials: L
authors.lastname: Luo
authors.forename: Xiangping
authors.initials: X
authors.lastname: Qian
authors.forename: Steven D
authors.initials: SD
authors.lastname: Knight
authors.forename: Neysa
authors.initials: N
authors.lastname: Nevins
authors.forename: Katjusa
authors.initials: K
authors.lastname: Brejc
authors.forename: David
authors.initials: D
authors.lastname: Sutton
authors.forename: Aidan G
authors.initials: AG
authors.lastname: Gilmartin
authors.forename: Penelope R
authors.initials: PR
authors.lastname: Chua
authors.forename: Radhika
authors.initials: R
authors.lastname: Desai
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Schauer
authors.forename: Dean E
authors.initials: DE
authors.lastname: McNulty
authors.forename: Roland S
authors.initials: RS
authors.lastname: Annan
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Belmont
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia
authors.forename: Yan
authors.initials: Y
authors.lastname: Lee
authors.forename: Melody A
authors.initials: MA
authors.lastname: Diamond
authors.forename: Leo F
authors.initials: LF
authors.lastname: Faucette
authors.forename: Michele
authors.initials: M
authors.lastname: Giardiniere
authors.forename: Shuyun
authors.initials: S
authors.lastname: Zhang
authors.forename: Chiu-Mei
authors.initials: CM
authors.lastname: Sun
authors.forename: Justin D
authors.initials: JD
authors.lastname: Vidal
authors.forename: Serge
authors.initials: S
authors.lastname: Lichtsteiner
authors.forename: William D
authors.initials: WD
authors.lastname: Cornwell
authors.forename: Joel D
authors.initials: JD
authors.lastname: Greshock
authors.forename: Richard F
authors.initials: RF
authors.lastname: Wooster
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Finer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: Pearl S
authors.initials: PS
authors.lastname: Huang
authors.forename: David J
authors.initials: DJ
authors.lastname: Morgans
authors.forename: Dashyant
authors.initials: D
authors.lastname: Dhanak
authors.forename: Gustave
authors.initials: G
authors.lastname: Bergnes
authors.forename: Roman
authors.initials: R
authors.lastname: Sakowicz
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jackson
mesh_terms: D000495:Allosteric Site; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D066298:In Vitro Techniques; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002868:Chromosomal Proteins, Non-Histone; C571460:GSK923295; C068688:centromere protein E; D016547:Kinesins; D012521:Sarcosine