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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
20
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pubmed:dateCreated |
2007-9-27
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AdamsNicholas DND,
pubmed-author:AugerKurt RKR,
pubmed-author:BurgessJoelle LJL,
pubmed-author:CarsonJeffrey DJD,
pubmed-author:ChaudhariAmita MAM,
pubmed-author:CopelandRobert ARA,
pubmed-author:DhanakDashyantD,
pubmed-author:DiamondMelody AMA,
pubmed-author:DonatelliCarla ACA,
pubmed-author:DuffyKevin JKJ,
pubmed-author:FaucetteLeo FLF,
pubmed-author:FinerJeffrey TJT,
pubmed-author:HuffmanWilliam FWF,
pubmed-author:HuggerErin DED,
pubmed-author:JacksonJeffrey RJR,
pubmed-author:KnightSteven DSD,
pubmed-author:LuoLusongL,
pubmed-author:MooreMichael LML,
pubmed-author:NewlanderKen AKA,
pubmed-author:ParrishCynthia ACA,
pubmed-author:RidgersLance HLH,
pubmed-author:SakowiczRomanR,
pubmed-author:ShawAntony NAN,
pubmed-author:SungChiu-Mei MCM,
pubmed-author:SuttonDavidD,
pubmed-author:WoodKenneth WKW,
pubmed-author:ZhangShu-YunSY,
pubmed-author:ZimmermanMichael NMN
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pubmed:issnType |
Print
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pubmed:day |
4
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pubmed:volume |
50
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4939-52
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pubmed:meshHeading |
pubmed-meshheading:17725339-Adenosine Triphosphate,
pubmed-meshheading:17725339-Animals,
pubmed-meshheading:17725339-Antineoplastic Agents,
pubmed-meshheading:17725339-Biphenyl Compounds,
pubmed-meshheading:17725339-Cell Line, Tumor,
pubmed-meshheading:17725339-Cell Proliferation,
pubmed-meshheading:17725339-Drug Screening Assays, Antitumor,
pubmed-meshheading:17725339-Female,
pubmed-meshheading:17725339-Humans,
pubmed-meshheading:17725339-Kinesin,
pubmed-meshheading:17725339-Mice,
pubmed-meshheading:17725339-Mice, Nude,
pubmed-meshheading:17725339-Mutation,
pubmed-meshheading:17725339-Neoplasm Transplantation,
pubmed-meshheading:17725339-Structure-Activity Relationship,
pubmed-meshheading:17725339-Sulfonamides
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pubmed:year |
2007
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pubmed:articleTitle |
Novel ATP-competitive kinesin spindle protein inhibitors.
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pubmed: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
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pubmed:publicationType |
Journal Article
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