3HP5

Crystal Structure of Human p38alpha complexed with a pyrimidopyridazinone compound

Summary for 3HP5

• Entry DOI: 10.2210/pdb3hp5/pdb
• Related: 3HLL 3HP2
• Descriptor: Mitogen-activated protein kinase 14, 5-(2,6-dichlorophenyl)-2-[(2,4-difluorophenyl)sulfanyl]-6H-pyrimido[1,6-b]pyridazin-6-one, 2-fluoro-4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine, ... (4 entities in total)
• Functional Keywords: two lobes, three ligands, three binding sites, distal and extra sites. peptide flip, atp-binding, kinase, nucleotide-binding, nucleus, phosphoprotein, serine/threonine-protein kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : Q16539
• Total number of polymer chains: 1
• Total formula weight: 42293.93

Authors

Shieh, H.-S.,Williams, J.M.,Stegeman, R.A.,Kurumbail, R.G. (deposition date: 2009-06-03, release date: 2009-09-29, Last modification date: 2024-02-21)

Primary citation

Selness, S.R.,Devraj, R.V.,Monahan, J.B.,Boehm, T.L.,Walker, J.K.,Devadas, B.,Durley, R.C.,Kurumbail, R.,Shieh, H.,Xing, L.,Hepperle, M.,Rucker, P.V.,Jerome, K.D.,Benson, A.G.,Marrufo, L.D.,Madsen, H.M.,Hitchcock, J.,Owen, T.J.,Christie, L.,Promo, M.A.,Hickory, B.S.,Alvira, E.,Naing, W.,Blevis-Bal, R.
Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase.
Bioorg.Med.Chem.Lett., 19:5851-5856, 2009

PubMed Abstract: The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38alpha. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation.

PubMed: 19751974
DOI: 10.1016/j.bmcl.2009.08.082

Experimental method

X-RAY DIFFRACTION (2.3 Å)