6SFJ

Crystal structure of p38 alpha in complex with compound 77 (MCP41)

6SFJ の概要

• エントリーDOI: 10.2210/pdb6sfj/pdb
• 分子名称: Mitogen-activated protein kinase 14, ~{N}-[5-[[(2~{S})-1-azanyl-4-cyclohexyl-1-oxidanylidene-butan-2-yl]carbamoyl]-2-methyl-phenyl]-1-(2-methylphenyl)pyrazole-4-carboxamide (3 entities in total)
• 機能のキーワード: p38a, mapk, mapk14, kinase inhibitor, structural genomics, structural genomics consortium, sgc, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41896.83

構造登録者

Chaikuad, A.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2019-08-01, 公開日: 2019-09-11, 最終更新日: 2024-01-24)

主引用文献

Rohm, S.,Berger, B.T.,Schroder, M.,Chaikuad, A.,Winkel, R.,Hekking, K.F.W.,Benningshof, J.J.C.,Muller, G.,Tesch, R.,Kudolo, M.,Forster, M.,Laufer, S.,Knapp, S.
Fast Iterative Synthetic Approach toward Identification of Novel Highly Selective p38 MAP Kinase Inhibitors.
J.Med.Chem., 62:10757-10782, 2019

PubMed Abstract: p38 mitogen-activated protein kinases are key mediators of environmental stress response and are promising targets for treatment of inflammatory diseases and cancer. Numerous efforts have led to the discovery of several potent inhibitors; however, so far no highly selective type-II inhibitors have been reported. We previously identified VPC-00628 as a potent and selective type-II inhibitor of p38α/β with few off-targets. Here we analyzed the chemical building blocks of VPC-00628 that played a key role in achieving potency and selectivity through targeting an inactive state of the kinases induced by a unique folded P-loop conformation. Using a rapid, systematic combinatorial synthetic approach, we identified compound () with excellent potency and selectivity for p38α/β, which potently inhibited the TNF-α release in whole blood. therefore presents a potent and selective type-II inhibitor of p38α/β that can be used as a chemical probe for targeting this particular inactive state of these two p38 isoforms.

PubMed: 31702918
DOI: 10.1021/acs.jmedchem.9b01227

実験手法

X-RAY DIFFRACTION (1.95 Å)