PDBsum entry 6emh

Transferase

PDB id: 6emh

Contents

Protein chains

344 a.a.

Ligands

BME ×3

BGE ×4

EDO ×5

C15 ×2

PEG ×2

GOL ×3

Metals

_CL ×3

Waters ×861

References listed in PDB file

Key reference

• Title: Structural optimization of a pyridinylimidazole scaffold: shifting the selectivity from p38α mitogen-Activated protein kinase to c-Jun n-Terminal kinase 3.
• Authors: F.Ansideri, J.T.Macedo, M.Eitel, A.El-Gokha, D.S.Zinad, C.Scarpellini, M.Kudolo, D.Schollmeyer, F.M.Boeckler, B.S.Blaum, S.A.Laufer, P.Koch.
• Ref.: ACS Omega, 2018, 3, 7809-7831.
• PubMed id: 30087925

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)-1H-imidazol-5-yl)-N-(4-morpholinophenyl)pyridin-2-amine showed an IC₅₀ value for the JNK3 in the low triple digit nanomolar range and its binding mode was confirmed by X-ray crystallography.