PDBsum entry 2gfs

Signaling protein, transferase

PDB id: 2gfs

Contents

Protein chain

344 a.a. *

Ligands

PQB

Waters ×293

* Residue conservation analysis

PDB id:

2gfs

Name:

Signaling protein, transferase

Title:

P38 kinase crystal structure in complex with ro3201195

Structure:

Mitogen-activated protein kinase 14. Chain: a. Synonym: mitogen-activated protein kinase p38 alpha. Map kinase p38 alpha. Cytokine suppressive anti-inflammatory drug-binding protein. Csaid-binding protein. Csbp. Max-interacting protein 2. Map kinase mxi2. Sapk2a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk14, csbp, csbp1, csbp2, mxi2. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.75Å R-factor: 0.205 R-free: 0.239

Authors:

S.F.Harris,J.Bertrand,A.Villasenor

Key ref:

D.M.Goldstein et al. (2006). Discovery of S-[5-amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3-dihydroxypropoxy)phenyl]methanone (RO3201195), an orally bioavailable and highly selective inhibitor of p38 MAP kinase. J Med Chem, 49, 1562-1575. PubMed id: 16509574 DOI: 10.1021/jm050736c

Date:

23-Mar-06 Release date: 18-Apr-06

Protein chain

Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14 from Homo sapiens

Seq: 360 a.a.

Struc: 344 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.24 - mitogen-activated protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm050736c

J Med Chem 49:1562-1575 (2006)

PubMed id: 16509574

Discovery of S-[5-amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3-dihydroxypropoxy)phenyl]methanone (RO3201195), an orally bioavailable and highly selective inhibitor of p38 MAP kinase.

D.M.Goldstein, T.Alfredson, J.Bertrand, M.F.Browner, K.Clifford, S.A.Dalrymple, J.Dunn, J.Freire-Moar, S.Harris, S.S.Labadie, J.La Fargue, J.M.Lapierre, S.Larrabee, F.Li, E.Papp, D.McWeeney, C.Ramesha, R.Roberts, D.Rotstein, B.San Pablo, E.B.Sjogren, O.Y.So, F.X.Talamas, W.Tao, A.Trejo, A.Villasenor, M.Welch, T.Welch, P.Weller, P.E.Whiteley, K.Young, S.Zipfel.

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.