3HRB

p38 kinase Crystal structure in complex with small molecule inhibitor

Summary for 3HRB

• Entry DOI: 10.2210/pdb3hrb/pdb
• Descriptor: Mitogen-activated protein kinase 14, [3-amino-2-(2-methylphenyl)-1-oxidopyridin-4-yl](2,4-difluorophenyl)methanone (3 entities in total)
• Functional Keywords: p38 map kinase, transferase, inhibitor complex, alternative splicing, atp-binding, cytoplasm, kinase, nucleotide-binding, nucleus, phosphoprotein, polymorphism, serine/threonine-protein kinase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm (By similarity): Q16539
• Total number of polymer chains: 1
• Total formula weight: 41552.32

Authors

Segarra, V.,Lumeras, W.,Vidal, B.,Leonard, P.,Fisher, M.,Lamers, M. (deposition date: 2009-06-09, release date: 2009-09-01, Last modification date: 2023-11-01)

Primary citation

Lumeras, W.,Caturla, F.,Vidal, L.,Esteve, C.,Balague, C.,Orellana, A.,Dominguez, M.,Roca, R.,Huerta, J.M.,Godessart, N.,Vidal, B.
Design, synthesis, and structure-activity relationships of aminopyridine N-oxides, a novel scaffold for the potent and selective inhibition of p38 mitogen activated protein kinase
J.Med.Chem., 52:5531-5545, 2009

PubMed Abstract: A novel series of aminopyridine N-oxides were designed, synthesized, and tested for their ability to inhibit p38alpha MAP kinase. Some of these compounds showed a significant reduction in the LPS-induced TNFalpha production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for a marked selectivity against other related kinases. Compound 45 was identified as a potent and selective p38alpha inhibitor with an appropriate balance between potency and pharmacokinetics. In vivo efficacy of 45 was demonstrated in reducing TNFalpha levels in an acute murine model of inflammation (ED(50) = 1 mg/kg in LPS-induced TNFalpha production when dosed orally 1.5 h prior to LPS administration). The oral efficacy of 45 was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) = 4.5 mg/kg).

PubMed: 19678708
DOI: 10.1021/jm9008604

Experimental method

X-RAY DIFFRACTION (2.2 Å)