3U8W

Crystal Structure of p38a Mitogen-Activated Protein Kinase in Complex with a Triazolopyridazinone inhibitor

Summary for 3U8W

• Entry DOI: 10.2210/pdb3u8w/pdb
• Related: 1YQJ 3DS6 3DT1 3GFE 3ITZ 3LHJ
• Descriptor: Mitogen-activated protein kinase 14, 3-[3-(2-chloro-6-fluorophenyl)-5-ethyl-6-oxo-5,6-dihydro[1,2,4]triazolo[4,3-b]pyridazin-7-yl]-N-cyclopropyl-4-methylbenzamide (3 entities in total)
• Functional Keywords: serine/threonine protein kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q16539
• Total number of polymer chains: 1
• Total formula weight: 42464.85

Authors

Mohr, C.,Jordan, S. (deposition date: 2011-10-17, release date: 2012-08-29, Last modification date: 2024-02-28)

Primary citation

Herberich, B.,Jackson, C.,Wurz, R.P.,Pettus, L.H.,Sherman, L.,Liu, Q.,Henkle, B.,Saris, C.J.,Wong, L.M.,Chmait, S.,Lee, M.R.,Mohr, C.,Hsieh, F.,Tasker, A.S.
Identification of triazolopyridazinones as potent p38alpha inhibitors.
Bioorg.Med.Chem.Lett., 22:1226-1229, 2012

PubMed Abstract: Structure-activity relationship (SAR) investigations of a novel class of triazolopyridazinone p38α mitogen activated protein kinase (MAPK) inhibitors are disclosed. From these studies, increased in vitro potency was observed for 2,6-disubstituted phenyl moieties and N-ethyl triazolopyridazinone cores due to key contacts with Leu108, Ala157 and Val38. Further investigation led to the identification of three compounds, 3g, 3j and 3m that are highly potent inhibitors of LPS-induced MAPKAP kinase 2 (MK2) phosphorylation in 50% human whole blood (hWB), and possess desirable in vivo pharmacokinetic and kinase selectivity profiles.

PubMed: 22196117
DOI: 10.1016/j.bmcl.2011.11.067

Experimental method

X-RAY DIFFRACTION (2.15 Å)