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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
10
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pubmed:dateCreated |
2010-5-20
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pubmed:abstractText |
The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with K(i)* values of 0.38 +/- 0.29 and 1.5 +/- 0.4 nM, respectively, and is >250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC(50) = 7 nM). Intraperitoneal administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clinical trials.
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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 |
May
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:AdamsJerry LJL,
pubmed-author:AdamsNicholas DND,
pubmed-author:BurgessJoelle LJL,
pubmed-author:ChaudhariAmita MAM,
pubmed-author:CopelandRobert ARA,
pubmed-author:DhanakDashyantD,
pubmed-author:DonatelliCarla ACA,
pubmed-author:DrewryDavid HDH,
pubmed-author:FisherKelly EKE,
pubmed-author:HamajimaToshihiroT,
pubmed-author:HardwickeMary AnnMA,
pubmed-author:HuffmanWilliam FWF,
pubmed-author:Koretke-BrownKristin KKK,
pubmed-author:LaiZhihong VZV,
pubmed-author:McDonaldOcterloney BOB,
pubmed-author:NakamuraHirokoH,
pubmed-author:NewlanderKen AKA,
pubmed-author:OleykowskiCatherine ACA,
pubmed-author:ParrishCynthia ACA,
pubmed-author:PatrickDenis RDR,
pubmed-author:PlantRamonaR,
pubmed-author:SarpongMartha AMA,
pubmed-author:SasakiKosukeK,
pubmed-author:SchmidtStanley JSJ,
pubmed-author:SilvaDomingos JDJ,
pubmed-author:SuttonDavidD,
pubmed-author:TangJunJ,
pubmed-author:ThompsonChristine SCS,
pubmed-author:TumminoPeter JPJ,
pubmed-author:WangJamin CJC,
pubmed-author:XiangHongH,
pubmed-author:YangJingsongJ
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pubmed:issnType |
Electronic
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pubmed:day |
27
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pubmed:volume |
53
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3973-4001
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pubmed:dateRevised |
2011-7-11
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pubmed:meshHeading |
pubmed-meshheading:20420387-Animals,
pubmed-meshheading:20420387-Aza Compounds,
pubmed-meshheading:20420387-Cell Line, Tumor,
pubmed-meshheading:20420387-Drug Screening Assays, Antitumor,
pubmed-meshheading:20420387-Histones,
pubmed-meshheading:20420387-Humans,
pubmed-meshheading:20420387-Indoles,
pubmed-meshheading:20420387-Mice,
pubmed-meshheading:20420387-Neoplasm Transplantation,
pubmed-meshheading:20420387-Phosphorylation,
pubmed-meshheading:20420387-Protein-Serine-Threonine Kinases,
pubmed-meshheading:20420387-Stereoisomerism,
pubmed-meshheading:20420387-Structure-Activity Relationship,
pubmed-meshheading:20420387-Transplantation, Heterologous
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pubmed:year |
2010
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pubmed:articleTitle |
Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase.
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pubmed:affiliation |
Cancer Research, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA. nicholas.d.adams@gsk.com
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pubmed:publicationType |
Journal Article
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