Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma.
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.
Pomel
Vincent
V
Department of Chemistry, Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland.
Klicic
Jasna
J
Covini
David
D
Church
Dennis D
DD
Shaw
Jeffrey P
JP
Roulin
Karen
K
Burgat-Charvillon
Fabienne
F
Valognes
Delphine
D
Camps
Montserrat
M
Chabert
Christian
C
Gillieron
Corinne
C
Françon
Bernard
B
Perrin
Dominique
D
Leroy
Didier
D
Gretener
Denise
D
Nichols
Anthony
A
Vitte
Pierre Alain
PA
Carboni
Susanna
S
Rommel
Christian
C
Schwarz
Matthias K
MK
Rückle
Thomas
T
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
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