Antitumor activity of an allosteric inhibitor of centromere-associated protein-E.
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.
Wood
Kenneth W
KW
Cytokinetics Inc, South San Francisco, CA 94080, USA. kwood@cytokinetics.com
Lad
Latesh
L
Luo
Lusong
L
Qian
Xiangping
X
Knight
Steven D
SD
Nevins
Neysa
N
Brejc
Katjusa
K
Sutton
David
D
Gilmartin
Aidan G
AG
Chua
Penelope R
PR
Desai
Radhika
R
Schauer
Stephen P
SP
McNulty
Dean E
DE
Annan
Roland S
RS
Belmont
Lisa D
LD
Garcia
Carlos
C
Lee
Yan
Y
Diamond
Melody A
MA
Faucette
Leo F
LF
Giardiniere
Michele
M
Zhang
Shuyun
S
Sun
Chiu-Mei
CM
Vidal
Justin D
JD
Lichtsteiner
Serge
S
Cornwell
William D
WD
Greshock
Joel D
JD
Wooster
Richard F
RF
Finer
Jeffrey T
JT
Copeland
Robert A
RA
Huang
Pearl S
PS
Morgans
David J
DJ
Dhanak
Dashyant
D
Bergnes
Gustave
G
Sakowicz
Roman
R
Jackson
Jeffrey R
JR
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
D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002868:Chromosomal Proteins, Non-Histone; C571460:GSK923295; C068688:centromere protein E; D016547:Kinesins; D012521:Sarcosine