Furan-2-ylmethylene Thiazolidinediones as Novel, Potent, and Selective Inhibitors of Phosphoinositide 3-Kinase γ Export

@article{citeulike:3404935, abstract = {Abstract: Class I phosphoinositide 3-kinases (PI3Ks), in particular PI3K, 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 PI3K inhibitors. Structure-based design and X-ray crystallography of complexes formed by inhibitors bound to PI3K 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 PI3K 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.}, address = {Departments of Chemistry, Signal Transduction, Biochemical Pharmacology, and Experimental Pharmacology, Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland}, author = {Pomel, V. and Klicic, J. and Covini, D. and Church, D. D. and Shaw, J. P. and Roulin, K. and Burgat-Charvillon, F. and Valognes, D. and Camps, M. and Chabert, C. and Gillieron, C. and Francon, B. and Perrin, D. and Leroy, D. and Gretener, D. and Nichols, A. and Vitte, P. A. and Carboni, S. and Rommel, C. and Schwarz, M. K. and Ruckle, T.}, citeulike-article-id = {3404935}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/jm0601598}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/jm0601598}, day = {29}, doi = {10.1021/jm0601598}, journal = {J. Med. Chem.}, keywords = {docking, flexibility, induced\_fit, scoring, virtual\_screening}, month = {June}, number = {13}, pages = {3857--3871}, posted-at = {2008-10-14 16:44:33}, priority = {2}, title = {Furan-2-ylmethylene Thiazolidinediones as Novel, Potent, and Selective Inhibitors of Phosphoinositide 3-Kinase \&\#x03B3;}, url = {http://dx.doi.org/10.1021/jm0601598}, volume = {49}, year = {2006} }

TY - JOUR ID - citeulike:3404935 L3 - citeulike-article-id:3404935 N2 - Abstract: Class I phosphoinositide 3-kinases (PI3Ks), in particular PI3K, 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 PI3K inhibitors. Structure-based design and X-ray crystallography of complexes formed by inhibitors bound to PI3K 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 PI3K 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. IS - 13 JF - J. Med. Chem. AD - Departments of Chemistry, Signal Transduction, Biochemical Pharmacology, and Experimental Pharmacology, Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland EP - 3871 TI - Furan-2-ylmethylene Thiazolidinediones as Novel, Potent, and Selective Inhibitors of Phosphoinositide 3-Kinase γ VL - 49 SP - 3857 KW - docking KW - flexibility KW - induced_fit KW - scoring KW - virtual_screening AU - Pomel, V AU - Klicic, J AU - Covini, D AU - Church, DD AU - Shaw, JP AU - Roulin, K AU - Burgat-Charvillon, F AU - Valognes, D AU - Camps, M AU - Chabert, C AU - Gillieron, C AU - Francon, B AU - Perrin, D AU - Leroy, D AU - Gretener, D AU - Nichols, A AU - Vitte, PA AU - Carboni, S AU - Rommel, C AU - Schwarz, MK AU - Ruckle, T PY - 2006/06/29/ UR - http://dx.doi.org/10.1021/jm0601598 ER -