2gfs: Difference between revisions

Revision as of 05:03, 4 May 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. 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 Page seeded by OCA on Sun May 4 05:03:28 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

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 [[Image:2gfs.gif|left|200px]]
- {{Structure
+<!--
-|PDB= 2gfs |SIZE=350|CAPTION= <scene name='initialview01'>2gfs</scene>, resolution 1.752&Aring;
+The line below this paragraph, containing "STRUCTURE_2gfs", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=PQB:[5-AMINO-1-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL](3-{[(2R)-2,3-DIHYDROXYPROPYL]OXY}PHENYL)METHANONE'>PQB</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[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] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE= MAPK14, CSBP, CSBP1, CSBP2, MXI2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
+-->
-|DOMAIN=
+{{STRUCTURE_2gfs|  PDB=2gfs  |  SCENE=  }}
-|RELATEDENTRY=
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2gfs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gfs OCA], [http://www.ebi.ac.uk/pdbsum/2gfs PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2gfs RCSB]</span>
-}}
 '''P38 Kinase Crystal Structure in complex with RO3201195'''
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 [[Category: Harris, S F.]]
 [[Category: Villasenor, A.]]
-[[Category: map kinase]]
+[[Category: Map kinase]]
-[[Category: p38]]
+[[Category: P38]]
-[[Category: serine/threonine kinase]]
+[[Category: Serine/threonine kinase]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 05:03:28 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:16:00 2008''