Novel ATP-competitive kinesin spindle protein inhibitors.
Kinesin spindle protein (KSP), an ATPase responsible for spindle pole separation during mitosis that is present only in proliferating cells, has become a novel and attractive anticancer target with potential for reduced side effects compared to currently available therapies. We report herein the discovery of the first known ATP-competitive inhibitors of KSP, which display a unique activity profile as compared to the known loop 5 (L5) allosteric KSP inhibitors that are currently under clinical evaluation. Optimization of this series led to the identification of biphenyl sulfamide 20, a potent KSP inhibitor with in vitro antiproliferative activity against human cells with either wild-type KSP (HCT116) or mutant KSP (HCT116 D130V). In a murine xenograft model with HCT116 D130V tumors, 20 showed significant antitumor activity following intraperitoneal dosing, providing in vivo proof-of-principle of the efficacy of an ATP-competitive KSP inhibitor versus tumors that are resistant to the other known KSP inhibitors.
Parrish
Cynthia A
CA
Department of Medicinal Chemistry, Oncology Center of Excellence for Drug Discovery, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. cynthia.a.parrish@gsk.com
Adams
Nicholas D
ND
Auger
Kurt R
KR
Burgess
Joelle L
JL
Carson
Jeffrey D
JD
Chaudhari
Amita M
AM
Copeland
Robert A
RA
Diamond
Melody A
MA
Donatelli
Carla A
CA
Duffy
Kevin J
KJ
Faucette
Leo F
LF
Finer
Jeffrey T
JT
Huffman
William F
WF
Hugger
Erin D
ED
Jackson
Jeffrey R
JR
Knight
Steven D
SD
Luo
Lusong
L
Moore
Michael L
ML
Newlander
Ken A
KA
Ridgers
Lance H
LH
Sakowicz
Roman
R
Shaw
Antony N
AN
Sung
Chiu-Mei M
CM
Sutton
David
D
Wood
Kenneth W
KW
Zhang
Shu-Yun
SY
Zimmerman
Michael N
MN
Dhanak
Dashyant
D
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; C470243:KIF11 protein, human; C524182:N-(4'-(trifluoromethyl)-4-biphenylyl)sulfamide; D013449:Sulfonamides; D000255:Adenosine Triphosphate; D016547:Kinesins