title: Novel ATP-competitive kinesin spindle protein inhibitors.
abstract: 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.
authors.affiliation: 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
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Parrish
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Adams
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Auger
authors.forename: Joelle L
authors.initials: JL
authors.lastname: Burgess
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Carson
authors.forename: Amita M
authors.initials: AM
authors.lastname: Chaudhari
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: Melody A
authors.initials: MA
authors.lastname: Diamond
authors.forename: Carla A
authors.initials: CA
authors.lastname: Donatelli
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Duffy
authors.forename: Leo F
authors.initials: LF
authors.lastname: Faucette
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Finer
authors.forename: William F
authors.initials: WF
authors.lastname: Huffman
authors.forename: Erin D
authors.initials: ED
authors.lastname: Hugger
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jackson
authors.forename: Steven D
authors.initials: SD
authors.lastname: Knight
authors.forename: Lusong
authors.initials: L
authors.lastname: Luo
authors.forename: Michael L
authors.initials: ML
authors.lastname: Moore
authors.forename: Ken A
authors.initials: KA
authors.lastname: Newlander
authors.forename: Lance H
authors.initials: LH
authors.lastname: Ridgers
authors.forename: Roman
authors.initials: R
authors.lastname: Sakowicz
authors.forename: Antony N
authors.initials: AN
authors.lastname: Shaw
authors.forename: Chiu-Mei M
authors.initials: CM
authors.lastname: Sung
authors.forename: David
authors.initials: D
authors.lastname: Sutton
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Wood
authors.forename: Shu-Yun
authors.initials: SY
authors.lastname: Zhang
authors.forename: Michael N
authors.initials: MN
authors.lastname: Zimmerman
authors.forename: Dashyant
authors.initials: D
authors.lastname: Dhanak
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; C470243:KIF11 protein, human; C524182:N-(4'-(trifluoromethyl)-4-biphenylyl)sulfamide; D013449:Sulfonamides; D000255:Adenosine Triphosphate; D016547:Kinesins