2GFS

P38 Kinase Crystal Structure in complex with RO3201195

2GFS の概要

• エントリーDOI: 10.2210/pdb2gfs/pdb
• 分子名称: 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)
• 機能のキーワード: p38; map kinase; serine/threonine kinase, signaling protein, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm : Q16539
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43120.08

構造登録者

Harris, S.F.,Bertrand, J.,Villasenor, A. (登録日: 2006-03-23, 公開日: 2006-04-18, 最終更新日: 2024-02-14)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.752 Å)