2GFS

P38 Kinase Crystal Structure in complex with RO3201195

Summary for 2GFS

• Entry DOI: 10.2210/pdb2gfs/pdb
• Descriptor: Mitogen-Activated Protein Kinase 14, [5-AMINO-1-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL](3-{[(2R)-2,3-DIHYDROXYPROPYL]OXY}PHENYL)METHANONE (3 entities in total)
• Functional Keywords: p38; map kinase; serine/threonine kinase, signaling protein, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : Q16539
• Total number of polymer chains: 1
• Total formula weight: 43120.08

Authors

Harris, S.F.,Bertrand, J.,Villasenor, A. (deposition date: 2006-03-23, release date: 2006-04-18, Last modification date: 2024-02-14)

Primary citation

Goldstein, D.M.,Alfredson, T.A.,Bertrand, J.,Browner, M.F.,Clifford, K.,Dalrymple, S.,Dunn, J.,Freire-Moare, J.,Harris, S.F.,Labadie, S.S.,La Fargue, J.,Lapierre, J.M.,Larrabee, S.,Li, F.,Papp, E.,McWeeney, D.,Ramesha, C.,Roberts, R.,Rotstein, D.,San Pablo, B.,Sjogren, E.,So, O.Y.,Talamas, F.X.,Tao, W.,Trejo, A.,Villasenor, A.,Welch, M.,Welch, T.,Weller, P.,Whiteley, P.E.,Young, K.,Zipfel, S.
Discovery of S-[5-Amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3-dihydroxypropoxy)phenyl]-methanone (RO3201195), and Orally Bioavailable and Highly Selective Inhibitor of p38 Map Kinase
J.Med.Chem., 49:1562-1575, 2006

PubMed Abstract: 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.

PubMed: 16509574
DOI: 10.1021/jm050736c

Experimental method

X-RAY DIFFRACTION (1.752 Å)