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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 |
2009-5-22
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pubmed:databankReference |
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pubmed:abstractText |
The two major Aurora kinases carry out critical functions at distinct mitotic stages. Selective inhibitors of these kinases, as well as pan-Aurora inhibitors, show antitumor efficacy and are now under clinical investigation. However, the ATP-binding sites of Aurora A and Aurora B are virtually identical, and the structural basis for selective inhibition has therefore not been clear. We report here a class of bisanilinopyrimidine Aurora A inhibitors with excellent selectivity for Aurora A over Aurora B, both in enzymatic assays and in cellular phenotypic assays. Crystal structures of two of the inhibitors in complex with Aurora A implicate a single amino acid difference in Aurora B as responsible for poor inhibitory activity against this enzyme. Mutation of this residue in Aurora B (E161T) or Aurora A (T217E) is sufficient to swap the inhibition profile, suggesting that this difference might be exploited more generally to achieve high selectivity for Aurora A.
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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:Aliagas-MartinIgnacioI,
pubmed-author:BurdickDanD,
pubmed-author:CochranAndrea GAG,
pubmed-author:CorsonLauraL,
pubmed-author:DotsonJennaferJ,
pubmed-author:DrummondJasonJ,
pubmed-author:FieldsCarterC,
pubmed-author:HuangOscar WOW,
pubmed-author:HunsakerThomasT,
pubmed-author:KleinheinzTracyT,
pubmed-author:KruegerElaineE,
pubmed-author:LiangJunJ,
pubmed-author:MoffatJohnJ,
pubmed-author:PhillipsGailG,
pubmed-author:PulkRebeccaR,
pubmed-author:RawsonThomas ETE,
pubmed-author:UltschMarkM,
pubmed-author:WalkerLeslieL,
pubmed-author:WiesmannChristianC,
pubmed-author:ZhangBirongB,
pubmed-author:ZhuBing-YanBY
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pubmed:issnType |
Electronic
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pubmed:day |
28
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pubmed:volume |
52
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3300-7
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pubmed:dateRevised |
2011-7-11
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pubmed:meshHeading |
pubmed-meshheading:19402633-Antineoplastic Agents,
pubmed-meshheading:19402633-Cell Line, Tumor,
pubmed-meshheading:19402633-Crystallography, X-Ray,
pubmed-meshheading:19402633-Drug Screening Assays, Antitumor,
pubmed-meshheading:19402633-Enzyme Inhibitors,
pubmed-meshheading:19402633-Humans,
pubmed-meshheading:19402633-Molecular Structure,
pubmed-meshheading:19402633-Protein Conformation,
pubmed-meshheading:19402633-Protein Kinase Inhibitors,
pubmed-meshheading:19402633-Protein-Serine-Threonine Kinases,
pubmed-meshheading:19402633-Pyrimidines,
pubmed-meshheading:19402633-Structure-Activity Relationship
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pubmed:year |
2009
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pubmed:articleTitle |
A class of 2,4-bisanilinopyrimidine Aurora A inhibitors with unusually high selectivity against Aurora B.
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pubmed:affiliation |
Department of Small Molecule Drug Discovery, 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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