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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2010-2-3
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pubmed:abstractText |
5-(Hetero)aryl-3-(4-carboxamidophenyl)-2-aminopyridine inhibitors of CHK2 were identified from high throughput screening of a kinase-focussed compound library. Rapid exploration of the hits through straightforward chemistry established structure-activity relationships and a proposed ATP-competitive binding mode which was verified by X-ray crystallography of several analogues bound to CHK2. Variation of the 5-(hetero)aryl substituent identified bicyclic dioxolane and dioxane groups which improved the affinity and the selectivity of the compounds for CHK2 versus CHK1. The 3-(4-carboxamidophenyl) substituent could be successfully replaced by acyclic omega-aminoalkylamides, which made additional polar interactions within the binding site and led to more potent inhibitors of CHK2. Compounds from this series showed activity in cell-based mechanistic assays for inhibition of CHK2.
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pubmed:grant |
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pubmed:commentsCorrections |
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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 |
Jan
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pubmed:issn |
1464-3391
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pubmed:author |
pubmed-author:AllenCharlotte ECE,
pubmed-author:AndersonVictoria EVE,
pubmed-author:AntoniLaurentL,
pubmed-author:BoxallKathyK,
pubmed-author:BurnsSamanthaS,
pubmed-author:CaldwellJohn JJJ,
pubmed-author:CollinsIanI,
pubmed-author:GarrettMichelle DMD,
pubmed-author:HiltonStephenS,
pubmed-author:NaudSebastienS,
pubmed-author:OliverAntony WAW,
pubmed-author:PearlLaurence HLH,
pubmed-author:Wynne AherneGG
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pubmed:copyrightInfo |
Copyright 2009 Elsevier Ltd. All rights reserved.
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pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
18
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
707-18
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pubmed:dateRevised |
2011-11-2
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pubmed:meshHeading |
pubmed-meshheading:20022510-Aminopyridines,
pubmed-meshheading:20022510-Binding Sites,
pubmed-meshheading:20022510-Cell Line,
pubmed-meshheading:20022510-Crystallography, X-Ray,
pubmed-meshheading:20022510-Humans,
pubmed-meshheading:20022510-Models, Molecular,
pubmed-meshheading:20022510-Molecular Structure,
pubmed-meshheading:20022510-Protein Kinase Inhibitors,
pubmed-meshheading:20022510-Protein-Serine-Threonine Kinases,
pubmed-meshheading:20022510-Stereoisomerism,
pubmed-meshheading:20022510-Structure-Activity Relationship
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pubmed:year |
2010
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pubmed:articleTitle |
Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2.
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pubmed:affiliation |
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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