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.
Subject(s)
Furans/chemical synthesis , Phosphoinositide-3 Kinase Inhibitors , Thiazolidinediones/chemical synthesis , Acute Disease , Animals , Bone Marrow Cells/drug effects , Bone Marrow Cells/physiology , Cells, Cultured , Chemotaxis/drug effects , Class Ib Phosphatidylinositol 3-Kinase , Crystallography, X-Ray , Furans/chemistry , Furans/pharmacology , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Mast Cells/drug effects , Mast Cells/metabolism , Mice , Models, Molecular , Molecular Structure , Monocytes/drug effects , Monocytes/physiology , Neutrophils/immunology , Peritonitis/chemically induced , Peritonitis/drug therapy , Peritonitis/immunology , Phosphatidylinositol 3-Kinases/chemistry , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Structure-Activity Relationship , Thiazolidinediones/chemistry , Thiazolidinediones/pharmacology , ThioglycolatesABSTRACT
Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystallized PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 A in nearly half of the cases and are greater than 2 A in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently described Surflex method.
