title: Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma.
abstract: 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.
authors.affiliation: Department of Chemistry, Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Pomel
authors.forename: Jasna
authors.initials: J
authors.lastname: Klicic
authors.forename: David
authors.initials: D
authors.lastname: Covini
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Church
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Shaw
authors.forename: Karen
authors.initials: K
authors.lastname: Roulin
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burgat-Charvillon
authors.forename: Delphine
authors.initials: D
authors.lastname: Valognes
authors.forename: Montserrat
authors.initials: M
authors.lastname: Camps
authors.forename: Christian
authors.initials: C
authors.lastname: Chabert
authors.forename: Corinne
authors.initials: C
authors.lastname: Gillieron
authors.forename: Bernard
authors.initials: B
authors.lastname: Françon
authors.forename: Dominique
authors.initials: D
authors.lastname: Perrin
authors.forename: Didier
authors.initials: D
authors.lastname: Leroy
authors.forename: Denise
authors.initials: D
authors.lastname: Gretener
authors.forename: Anthony
authors.initials: A
authors.lastname: Nichols
authors.forename: Pierre Alain
authors.initials: PA
authors.lastname: Vitte
authors.forename: Susanna
authors.initials: S
authors.lastname: Carboni
authors.forename: Christian
authors.initials: C
authors.lastname: Rommel
authors.forename: Matthias K
authors.initials: MK
authors.lastname: Schwarz
authors.forename: Thomas
authors.initials: T
authors.lastname: Rückle
mesh_terms: D000208:Acute Disease; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D058544:Class Ib Phosphatidylinositol 3-Kinase; D018360:Crystallography, X-Ray; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000276:immunology; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013864:Thioglycolates
chemical_list: D058544:Class Ib Phosphatidylinositol 3-Kinase; D005663:Furans; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D045162:Thiazolidinediones; D013864:Thioglycolates; C512438:5-(5-(4-fluoro-2-hydroxyphenyl)furan-2-ylmethylene)thiazolidine-2,4-dione; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse