2. Academic Validation
  3. Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma

Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma

  • J Med Chem. 2006 Jun 29;49(13):3857-71. doi: 10.1021/jm0601598.
Vincent Pomel 1,  Jasna Klicic,  David Covini,  Dennis D Church,  Jeffrey P Shaw,  Karen Roulin,  Fabienne Burgat-Charvillon,  Delphine Valognes,  Montserrat Camps,  Christian Chabert,  Corinne Gillieron,  Bernard Françon,  Dominique Perrin,  Didier Leroy,  Denise Gretener,  Anthony Nichols,  Pierre Alain Vitte,  Susanna Carboni,  Christian Rommel,  Matthias K Schwarz,  Thomas Rückle
Affiliations

Affiliation

  • 1 Department of Chemistry, Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland.
PMID: 16789742 DOI: 10.1021/jm0601598
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.

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