2gfs: Difference between revisions

Revision as of 18:31, 21 February 2008

P38 Kinase Crystal Structure in complex with RO3201195

OverviewOverview

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 StructureAbout this Structure

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

ReferenceReference

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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OCA

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 '''P38 Kinase Crystal Structure in complex with RO3201195'''<br />
 ==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.
+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==
-GFS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with PQB as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2GFS OCA].
+GFS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=PQB:'>PQB</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GFS OCA].
 ==Reference==
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 [[Category: Single protein]]
 [[Category: Bertrand, J.]]
-[[Category: Harris, S.F.]]
+[[Category: Harris, S F.]]
 [[Category: Villasenor, A.]]
 [[Category: PQB]]
 [[Category: p38; map kinase; serine/threonine kinase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:18:23 2007''
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