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rdf:type |
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lifeskim:mentions |
umls-concept:C0001480,
umls-concept:C0031727,
umls-concept:C0205147,
umls-concept:C0243077,
umls-concept:C0332307,
umls-concept:C0457406,
umls-concept:C1167622,
umls-concept:C1546856,
umls-concept:C1706053,
umls-concept:C1707719,
umls-concept:C2587213
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pubmed:issue |
19
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pubmed:dateCreated |
2010-9-13
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pubmed:abstractText |
Switch control pocket inhibitors of p38-alpha kinase are described. Durable type II inhibitors were designed which bind to arginines (Arg67 or Arg70) that function as key residues for mediating phospho-threonine 180 dependant conformational fluxing of p38-alpha from an inactive type II state to an active type I state. Binding to Arg70 in particular led to potent inhibitors, exemplified by DP-802, which also exhibited high kinase selectivity. Binding to Arg70 obviated the requirement for binding into the ATP Hinge region. X-ray crystallography revealed that DP-802 and analogs induce an enhanced type II conformation upon binding to either the unphosphorylated or the doubly phosphorylated form of p38-alpha kinase.
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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 |
1464-3405
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pubmed:author |
pubmed-author:AbendrothJanJ,
pubmed-author:AhnYu MiYM,
pubmed-author:ChunLawrenceL,
pubmed-author:ClareMichaelM,
pubmed-author:ClarkRobinR,
pubmed-author:EnsingerCarol LCL,
pubmed-author:FeeseMichaelM,
pubmed-author:FlynnDaniel LDL,
pubmed-author:HoodMolly MMM,
pubmed-author:KaufmanMichael DMD,
pubmed-author:KimHidongH,
pubmed-author:LordJohn WJW,
pubmed-author:LuWei-PingWP,
pubmed-author:MillerDavid FDF,
pubmed-author:PattWilliam CWC,
pubmed-author:PetilloPeter APA,
pubmed-author:SmithBryan DBD,
pubmed-author:StewartLanceL,
pubmed-author:VogetiLakshminarayanaL,
pubmed-author:WiseScott CSC
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pubmed:copyrightInfo |
Copyright © 2010 Elsevier Ltd. All rights reserved.
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pubmed:issnType |
Electronic
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pubmed:day |
1
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pubmed:volume |
20
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5793-8
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pubmed:meshHeading |
pubmed-meshheading:20800479-Adenosine Triphosphate,
pubmed-meshheading:20800479-Binding Sites,
pubmed-meshheading:20800479-Computer Simulation,
pubmed-meshheading:20800479-Crystallography, X-Ray,
pubmed-meshheading:20800479-HeLa Cells,
pubmed-meshheading:20800479-Humans,
pubmed-meshheading:20800479-Kinetics,
pubmed-meshheading:20800479-Mitogen-Activated Protein Kinase 14,
pubmed-meshheading:20800479-Phenylurea Compounds,
pubmed-meshheading:20800479-Phosphorylation,
pubmed-meshheading:20800479-Protein Binding,
pubmed-meshheading:20800479-Protein Kinase Inhibitors,
pubmed-meshheading:20800479-Pyrazoles,
pubmed-meshheading:20800479-Structure-Activity Relationship
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pubmed:year |
2010
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pubmed:articleTitle |
Switch control pocket inhibitors of p38-MAP kinase. Durable type II inhibitors that do not require binding into the canonical ATP hinge region.
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pubmed:affiliation |
Deciphera Pharmaceuticals LLC, 643 Massachusetts St, Lawrence, KS 66044, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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