2gfs

From Proteopedia

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Revision as of 20:11, 12 November 2007

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spinqualitylabelsall models 2gfs, resolution 1.752Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

P38 Kinase Crystal Structure in complex with RO3201195

Overview

A novel class of highly selective inhibitors of p38 MAP kinase was, discovered from high throughput screening. The synthesis and optimization, of a series of 5-amino-N-phenyl-1H-pyrazol-4-yl-3-phenylmethanones is, described. An X-ray crystal structure of this series bound in the ATP, binding pocket of unphosphorylated p38alpha established the presence of a, unique hydrogen bond between the exocyclic amine of the inhibitor and, threonine 106 which likely contributes to the selectivity for p38. The, crystallographic information was used to optimize the potency and, physicochemical properties of the series. The incorporation of the, 2,3-dihydroxypropoxy moiety on the pyrazole scaffold resulted in a, compound with excellent drug-like properties including high oral, bioavailability. These efforts identified 63 (RO3201195) as an orally, bioavailable and highly selective inhibitor of p38 which was selected for, advancement into Phase I clinical trials.

About this Structure

2GFS is a Single protein structure of sequence from Homo sapiens with PQB as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.

Reference

Discovery of S-[5-amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3-dihydroxypropoxy)ph enyl]methanone (RO3201195), an orally bioavailable and highly selective inhibitor of p38 MAP kinase., Goldstein DM, Alfredson T, Bertrand J, Browner MF, Clifford K, Dalrymple SA, Dunn J, Freire-Moar J, Harris S, Labadie SS, La Fargue J, Lapierre JM, Larrabee S, Li F, Papp E, McWeeney D, Ramesha C, Roberts R, Rotstein D, San Pablo B, Sjogren EB, So OY, Talamas FX, Tao W, Trejo A, Villasenor A, Welch M, Welch T, Weller P, Whiteley PE, Young K, Zipfel S, J Med Chem. 2006 Mar 9;49(5):1562-75. PMID:16509574

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