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

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Pomel V, Klicic J, Covini D, Church DD, Shaw JP, Roulin K, Burgat-Charvillon F, Valognes D, Camps M, Chabert C, Gillieron C, Francon B, Perrin D, Leroy D, Gretener D, Nichols A, Vitte PA, Carboni S, Rommel C, Schwarz MK, Ruckle T

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.

PubMed ID

16789742 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
LY-294002	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform	IC 50 (nM)	7260	N/A	N/A	Details
Wortmannin	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	IC 50 (nM)	1	N/A	N/A	Details
Wortmannin	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform	IC 50 (nM)	5	N/A	N/A	Details