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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
15
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pubmed:dateCreated |
2008-8-8
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pubmed:abstractText |
Aurora kinase inhibitors have attracted a great deal of interest as a new class of antimitotic agents. We report a novel class of Aurora inhibitors based on a pentacyclic scaffold. A prototype pentacyclic inhibitor 32 (AKI-001) derived from two early lead structures improves upon the best properties of each parent and compares favorably to a previously reported Aurora inhibitor, 39 (VX-680). The inhibitor exhibits low nanomolar potency against both Aurora A and Aurora B enzymes, excellent cellular potency (IC50 < 100 nM), and good oral bioavailability. Phenotypic cellular assays show that both Aurora A and Aurora B are inhibited at inhibitor concentrations sufficient to block proliferation. Importantly, the cellular activity translates to potent inhibition of tumor growth in vivo. An oral dose of 5 mg/kg QD is well tolerated and results in near stasis (92% TGI) in an HCT116 mouse xenograft model.
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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 |
Aug
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:BlackwoodElizabethE,
pubmed-author:BurdickDanD,
pubmed-author:CochranAndrea GAG,
pubmed-author:CorsonLauraL,
pubmed-author:DotsonJennaJ,
pubmed-author:DrummondJasonJ,
pubmed-author:FieldsCarterC,
pubmed-author:GeorgesGuy JGJ,
pubmed-author:GollerBernhardB,
pubmed-author:HalladayJasonJ,
pubmed-author:HunsakerThomasT,
pubmed-author:KleinheinzTracyT,
pubmed-author:KrellHans-WilliHW,
pubmed-author:LiangJunJ,
pubmed-author:LimbergAnjaA,
pubmed-author:McNuttAngelaA,
pubmed-author:MeeSS,
pubmed-author:MoffatJohnJ,
pubmed-author:PhillipsGailG,
pubmed-author:RügerPetraP,
pubmed-author:RüthMatthiasM,
pubmed-author:RanYingqingY,
pubmed-author:RawsonThomas ETE,
pubmed-author:SafinaBrianB,
pubmed-author:UltschMarkM,
pubmed-author:WalkerLeslieL,
pubmed-author:WiesmannChristianC,
pubmed-author:ZhangBirongB,
pubmed-author:ZhouAiheA,
pubmed-author:ZhuBing-YanBY
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pubmed:issnType |
Electronic
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pubmed:day |
14
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pubmed:volume |
51
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4465-75
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pubmed:dateRevised |
2011-7-11
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pubmed:meshHeading |
pubmed-meshheading:18630890-Administration, Oral,
pubmed-meshheading:18630890-Animals,
pubmed-meshheading:18630890-Benzimidazoles,
pubmed-meshheading:18630890-Biological Availability,
pubmed-meshheading:18630890-Cell Line, Tumor,
pubmed-meshheading:18630890-Crystallography, X-Ray,
pubmed-meshheading:18630890-Dogs,
pubmed-meshheading:18630890-Heterocyclic Compounds with 4 or More Rings,
pubmed-meshheading:18630890-Humans,
pubmed-meshheading:18630890-Lactams,
pubmed-meshheading:18630890-Mice,
pubmed-meshheading:18630890-Models, Molecular,
pubmed-meshheading:18630890-Molecular Structure,
pubmed-meshheading:18630890-Protein Kinase Inhibitors,
pubmed-meshheading:18630890-Protein-Serine-Threonine Kinases,
pubmed-meshheading:18630890-Rats
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pubmed:year |
2008
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pubmed:articleTitle |
A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability.
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pubmed:affiliation |
Departments of Small Molecule Drug DiscoVery, Cell Cycle and Global Regulators, Translational Oncology, and Protein Engineering, Genentech, Inc, 1 DNA Way, South San Francisco, California 94080, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, N.I.H., Extramural
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