5ML5

Human p38alpha MAPK in complex with imidazolyl pyridine inhibitor 11b

Summary for 5ML5

• Entry DOI: 10.2210/pdb5ml5/pdb
• Descriptor: 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)
• Functional Keywords: kinase, p38alpha, inhibitor, complex, ck1, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 42712.87

Authors

Buehrmann, M.,Rauh, D. (deposition date: 2016-12-06, release date: 2017-04-05, Last modification date: 2024-05-08)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.9 Å)