5ML5

Human p38alpha MAPK in complex with imidazolyl pyridine inhibitor 11b

5ML5 の概要

• エントリーDOI: 10.2210/pdb5ml5/pdb
• 分子名称: Mitogen-activated protein kinase 14, octyl beta-D-glucopyranoside, 3-(2,5-dimethoxyphenyl)-~{N}-[4-[4-(4-fluorophenyl)-2-methylsulfanyl-1~{H}-imidazol-5-yl]pyridin-2-yl]propanamide, ... (4 entities in total)
• 機能のキーワード: kinase, p38alpha, inhibitor, complex, ck1, 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: 42712.87

構造登録者

Buehrmann, M.,Rauh, D. (登録日: 2016-12-06, 公開日: 2017-04-05, 最終更新日: 2024-05-08)

主引用文献

Halekotte, J.,Witt, L.,Ianes, C.,Kruger, M.,Buhrmann, M.,Rauh, D.,Pichlo, C.,Brunstein, E.,Luxenburger, A.,Baumann, U.,Knippschild, U.,Bischof, J.,Peifer, C.
Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1 delta and Their Structural Relation to p38 alpha MAPK.
Molecules, 22:-, 2017

PubMed Abstract: The involvement of protein kinase CK1δ in the pathogenesis of severe disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and basic research. Unfortunately, the design of CK1 isoform-specific compounds has proved to be highly complicated due to the existence of six evolutionarily conserved human CK1 members that possess similar, different, or even opposite physiological and pathophysiological implications. Consequently, only few potent and selective CK1δ inhibitors have been reported so far and structurally divergent approaches are urgently needed in order to establish SAR that might enable complete discrimination of CK1 isoforms and related p38α MAPK. In this study we report on design and characterization of optimized 4,5-diarylimidazoles as highly effective ATP-competitive inhibitors of CK1δ with compounds 11b (IC CK1δ = 4 nM, IC CK1ε = 25 nM), 12a (IC CK1δ = 19 nM, IC CK1ε = 227 nM), and 16b (IC CK1δ = 8 nM, IC CK1ε = 81 nM) being among the most potent CK1δ-targeting agents published to date. Inhibitor compound , displaying potential as a pharmacological tool, has further been profiled over a panel of 321 protein kinases exhibiting high selectivity. Cellular efficacy has been evaluated in human pancreatic cancer cell lines Colo357 (EC = 3.5 µM) and Panc89 (EC = 1.5 µM). SAR is substantiated by X-ray crystallographic analysis of in CK1δ and in p38α.

PubMed: 28338621
DOI: 10.3390/molecules22040522

実験手法

X-RAY DIFFRACTION (1.9 Å)