3GFE

Crystal Structure of p38a Mitogen-Activated Protein Kinase in Complex with a Pyrazolopyridinone Inhibitor

Summary for 3GFE

• Entry DOI: 10.2210/pdb3gfe/pdb
• Related: 1YQJ 3DS6 3DT1
• Descriptor: Mitogen-activated protein kinase 14, N-cyclopropyl-3-{[1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}-4-methylbenzamide (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: 42448.39

Authors

Mohr, C.,Jordan, S. (deposition date: 2009-02-26, release date: 2009-07-14, Last modification date: 2024-02-21)

Primary citation

Wurz, R.P.,Pettus, L.H.,Xu, S.,Henkle, B.,Sherman, L.,Plant, M.,Miner, K.,McBride, H.,Wong, L.M.,Saris, C.J.,Lee, M.R.,Chmait, S.,Mohr, C.,Hsieh, F.,Tasker, A.S.
Part 1: 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., 19:4724-4728, 2009

PubMed Abstract: A novel class of fused pyrazole-derived inhibitors of p38alpha mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC(50) values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10 m and 10 q. Inhibitor 10 m was found to be efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of 0.1mg/kg while 10 q was found to have an ED(50) of 0.05-0.07 mg/kg.

PubMed: 19574047
DOI: 10.1016/j.bmcl.2009.06.058

Experimental method

X-RAY DIFFRACTION (2.1 Å)