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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
8
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pubmed:dateCreated |
2008-2-28
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pubmed:databankReference |
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pubmed:abstractText |
Analysis of the x-ray crystal structure of mono-substituted acetylenic thienopyrimidine 6 complexed with the ErbB family enzyme ErbB-4 revealed a covalent bond between the terminal carbon of the acetylene moiety and the sulfhydryl group of Cys-803 at the solvent interface. The identification of this covalent adduct suggested that acetylenic thienopyrimidine 6 and related analogs might also be capable of forming an analogous covalent adduct with EGFR, which has a conserved cysteine (797) near the ATP binding pocket. To test this hypothesis, we treated a truncated, catalytically competent form of EGFR (678-1020) with a structurally related propargylic amine (8). An investigation of the resulting complex by mass spectrometry revealed the formation of a covalent complex of thienopyrimidine 8 with Cys-797 of EGFR. This finding enabled us to readily assess the irreversibility of various inhibitors and also facilitated a structure-activity relationship understanding of the covalent modifying potential and biological activity of a series of acetylenic thienopyrimidine compounds with potent antitumor activity. Several ErbB family enzyme and cell potent 6-ethynyl thienopyrimidine kinase inhibitors were found to form covalent adducts with EGFR.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/18287036,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18287036-11585755,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18287036-11696537,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18287036-12171567,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18287036-12196540,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18287036-12467226,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18287036-12502359,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18287036-15374980,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18287036-15609371,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18287036-16777603,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18287036-17334377,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18287036-17349580,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18287036-9751783
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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 |
Feb
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pubmed:issn |
1091-6490
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pubmed:author |
pubmed-author:BrashearRonald LRL,
pubmed-author:BrignolaPerryP,
pubmed-author:CaferroThomas RTR,
pubmed-author:DickersonScott HSH,
pubmed-author:DicksonHamilton DHD,
pubmed-author:DonaldsonKelly HKH,
pubmed-author:EllisByronB,
pubmed-author:GaulMichaelM,
pubmed-author:GriffinRobert JRJ,
pubmed-author:HassellAnne MAM,
pubmed-author:KeithBarryB,
pubmed-author:MullinRobertR,
pubmed-author:PetrovKimberly GKG,
pubmed-author:RenoMichael JMJ,
pubmed-author:RusnakDavid WDW,
pubmed-author:ShewchukLisa MLM,
pubmed-author:TadepalliSarva MSM,
pubmed-author:UehlingDavid EDE,
pubmed-author:UlrichJohn CJC,
pubmed-author:VanderwallDana EDE,
pubmed-author:WagnerCraig DCD,
pubmed-author:WatersonAlex GAG,
pubmed-author:WhiteWendy LWL,
pubmed-author:WilliamsJon DJD,
pubmed-author:WoodEdgar RER
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pubmed:issnType |
Electronic
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pubmed:day |
26
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pubmed:volume |
105
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2773-8
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:18287036-Alkynes,
pubmed-meshheading:18287036-Aniline Compounds,
pubmed-meshheading:18287036-Animals,
pubmed-meshheading:18287036-Cell Proliferation,
pubmed-meshheading:18287036-Crystallography, X-Ray,
pubmed-meshheading:18287036-Dose-Response Relationship, Drug,
pubmed-meshheading:18287036-Female,
pubmed-meshheading:18287036-Isatin,
pubmed-meshheading:18287036-Mass Spectrometry,
pubmed-meshheading:18287036-Mice,
pubmed-meshheading:18287036-Mice, SCID,
pubmed-meshheading:18287036-Models, Molecular,
pubmed-meshheading:18287036-Molecular Structure,
pubmed-meshheading:18287036-Pyrimidines,
pubmed-meshheading:18287036-Receptor, Epidermal Growth Factor,
pubmed-meshheading:18287036-Receptor Protein-Tyrosine Kinases,
pubmed-meshheading:18287036-Structure-Activity Relationship,
pubmed-meshheading:18287036-Xenograft Model Antitumor Assays
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pubmed:year |
2008
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pubmed:articleTitle |
6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases.
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pubmed:affiliation |
Department of Assay Development, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
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pubmed:publicationType |
Journal Article,
Comparative Study
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