3ITZ
Crystal Structure of p38a Mitogen-Activated Protein Kinase in Complex with a Pyrazolopyridazine Inhibitor
Summary for 3ITZ
| Entry DOI | 10.2210/pdb3itz/pdb |
| Related | 1YQJ 3DS6 3DT1 3GFE |
| Descriptor | Mitogen-activated protein kinase 14, 4-chloro-N-cyclopropyl-3-{[1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-d]pyridazin-4-yl]amino}benzamide (3 entities in total) |
| Functional Keywords | serine/threonine-protein kinase, transferase, alternative splicing, atp-binding, cytoplasm, kinase, nucleotide-binding, nucleus, phosphoprotein, polymorphism |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm (By similarity): Q16539 |
| Total number of polymer chains | 1 |
| Total formula weight | 42439.77 |
| Authors | Mohr, C.,Jordan, S. (deposition date: 2009-08-28, release date: 2010-03-02, Last modification date: 2024-02-21) |
| Primary citation | Wurz, R.P.,Pettus, L.H.,Henkle, B.,Sherman, L.,Plant, M.,Miner, K.,McBride, H.J.,Wong, L.M.,Saris, C.J.,Lee, M.R.,Chmait, S.,Mohr, C.,Hsieh, F.,Tasker, A.S. Part 2: Structure-activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38alpha mitogen-activated protein kinase. Bioorg.Med.Chem.Lett., 20:1680-1684, 2010 Cited by PubMed Abstract: A novel class of pyrazolopyridazine p38alpha mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC(50) values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38alpha inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38alpha/beta over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of ca. 0.08mg/kg. PubMed: 20138761DOI: 10.1016/j.bmcl.2010.01.059 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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