6EMH

Crystal structure of JNK3 in complex with a pyridinylimidazole inhibitor

Summary for 6EMH

• Entry DOI: 10.2210/pdb6emh/pdb
• Descriptor: Mitogen-activated protein kinase 10, BETA-MERCAPTOETHANOL, CHLORIDE ION, ... (9 entities in total)
• Functional Keywords: protein kinase activity map kinase activity atp binding protein phosphorylation, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 172197.76

Authors

Macedo, J.T.,Stehle, T.,Blaum, B.S. (deposition date: 2017-10-02, release date: 2018-08-08, Last modification date: 2024-01-17)

Primary citation

Ansideri, F.,Macedo, J.T.,Eitel, M.,El-Gokha, A.,Zinad, D.S.,Scarpellini, C.,Kudolo, M.,Schollmeyer, D.,Boeckler, F.M.,Blaum, B.S.,Laufer, S.A.,Koch, P.
Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38 alpha Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3.
ACS Omega, 3:7809-7831, 2018

PubMed Abstract: Starting from known p38α mitogen-activated protein kinase (MAPK) inhibitors, a series of inhibitors of the c-Jun N-terminal kinase (JNK) 3 was obtained. Altering the substitution pattern of the pyridinylimidazole scaffold proved to be effective in shifting the inhibitory activity from the original target p38α MAPK to the closely related JNK3. In particular, a significant improvement for JNK3 selectivity could be achieved by addressing the hydrophobic region I with a small methyl group. Furthermore, additional structural modifications permitted to explore structure-activity relationships. The most potent inhibitor 4-(4-methyl-2-(methylthio)-1-imidazol-5-yl)--(4-morpholinophenyl)pyridin-2-amine showed an IC value for the JNK3 in the low triple digit nanomolar range and its binding mode was confirmed by X-ray crystallography.

PubMed: 30087925
DOI: 10.1021/acsomega.8b00668

Experimental method

X-RAY DIFFRACTION (1.76 Å)