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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
13
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pubmed:dateCreated |
2006-6-22
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pubmed:abstractText |
Class I phosphoinositide 3-kinases (PI3Ks), in particular PI3Kgamma, have become attractive drug targets for inflammatory and autoimmune diseases. Here, we disclose a novel series of furan-2-ylmethylene thiazolidinediones as selective, ATP-competitive PI3Kgamma inhibitors. Structure-based design and X-ray crystallography of complexes formed by inhibitors bound to PI3Kgamma identified key pharmacophore features for potency and selectivity. An acidic NH group on the thiazolidinedione moiety and a hydroxy group on the furan-2-yl-phenyl part of the molecule play crucial roles in binding to PI3K and contribute to class IB PI3K selectivity. Compound 26 (AS-252424), a potent and selective small-molecule PI3Kgamma inhibitor emerging from these efforts, was further profiled in three different cellular PI3K assays and shown to be selective for class IB PI3K-mediated cellular effects. Oral administration of 26 in a mouse model of acute peritonitis led to a significant reduction of leukocyte recruitment.
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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 |
http://linkedlifedata.com/resource/pubmed/chemical/Class Ib Phosphatidylinositol...,
http://linkedlifedata.com/resource/pubmed/chemical/Furans,
http://linkedlifedata.com/resource/pubmed/chemical/Isoenzymes,
http://linkedlifedata.com/resource/pubmed/chemical/PIK3CG protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Pik3cg protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Thiazolidinediones,
http://linkedlifedata.com/resource/pubmed/chemical/Thioglycolates
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:Burgat-CharvillonFabienneF,
pubmed-author:CampsMontserratM,
pubmed-author:CarboniSusannaS,
pubmed-author:ChabertChristianC,
pubmed-author:ChurchDennis DDD,
pubmed-author:CoviniDavidD,
pubmed-author:FrançonBernardB,
pubmed-author:GillieronCorinneC,
pubmed-author:GretenerDeniseD,
pubmed-author:KlicicJasnaJ,
pubmed-author:LeroyDidierD,
pubmed-author:NicholsAnthonyA,
pubmed-author:PerrinDominiqueD,
pubmed-author:PomelVincentV,
pubmed-author:RückleThomasT,
pubmed-author:RommelChristianC,
pubmed-author:RoulinKarenK,
pubmed-author:SchwarzMatthias KMK,
pubmed-author:ShawJeffrey PJP,
pubmed-author:ValognesDelphineD,
pubmed-author:VittePierre AlainPA
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pubmed:issnType |
Print
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pubmed:day |
29
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pubmed:volume |
49
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3857-71
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:16789742-Acute Disease,
pubmed-meshheading:16789742-Animals,
pubmed-meshheading:16789742-Bone Marrow Cells,
pubmed-meshheading:16789742-Cells, Cultured,
pubmed-meshheading:16789742-Chemotaxis,
pubmed-meshheading:16789742-Class Ib Phosphatidylinositol 3-Kinase,
pubmed-meshheading:16789742-Crystallography, X-Ray,
pubmed-meshheading:16789742-Furans,
pubmed-meshheading:16789742-Humans,
pubmed-meshheading:16789742-Isoenzymes,
pubmed-meshheading:16789742-Mast Cells,
pubmed-meshheading:16789742-Mice,
pubmed-meshheading:16789742-Models, Molecular,
pubmed-meshheading:16789742-Molecular Structure,
pubmed-meshheading:16789742-Monocytes,
pubmed-meshheading:16789742-Neutrophils,
pubmed-meshheading:16789742-Peritonitis,
pubmed-meshheading:16789742-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:16789742-Phosphorylation,
pubmed-meshheading:16789742-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:16789742-Structure-Activity Relationship,
pubmed-meshheading:16789742-Thiazolidinediones,
pubmed-meshheading:16789742-Thioglycolates
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pubmed:year |
2006
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pubmed:articleTitle |
Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma.
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pubmed:affiliation |
Department of Chemistry, Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland.
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pubmed:publicationType |
Journal Article
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