Dataset Information

Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38? Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3.

ABSTRACT: Starting from known p38? 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 p38? 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.

SUBMITTER: Ansideri F

PROVIDER: S-EPMC6072243 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38α Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3.

Ansideri Francesco F Macedo Joana T JT Eitel Michael M El-Gokha Ahmed A Zinad Dhafer S DS Scarpellini Camilla C Kudolo Mark M Schollmeyer Dieter D Boeckler Frank M FM Blaum Bärbel S BS Laufer Stefan A SA Koch Pierre P

ACS omega 20180712 7

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. Furthermo ...[more]

PMID: 30087925

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Project description:The expression of the c-jun proto-oncogene is rapidly induced in response to mitogens acting on a large variety of cell surface receptors. The resulting functional activity of c-Jun proteins appears to be critical for cell proliferation. Recently, we have shown that a large family of G protein-coupled receptors (GPCRs), represented by the m1 muscarinic receptor, can initiate intracellular signaling cascades that result in the activation of mitogen-activated protein kinases (MAPK) and c-Jun NH2-terminal kinases (JNK) and that the activation of JNK but not of MAPK correlated with a remarkable increase in the expression of c-jun mRNA. Subsequently, however, we obtained evidence that GPCRs can potently stimulate the activity of the c-jun promoter through MEF2 transcription factors, which do not act downstream from JNK. In view of these observations, we set out to investigate further the nature of the signaling pathway linking GPCRs to the c-jun promoter. Utilizing NIH 3T3 cells, we found that GPCRs can activate the c-jun promoter in a JNK-independent manner. Additionally, we demonstrated that these GPCRs can elevate the activity of novel members of the MAPK family, including ERK5, p38alpha, p38gamma, and p38delta, and that the activation of certain kinases acting downstream from MEK5 (ERK5) and MKK6 (p38alpha and p38gamma) is necessary to fully activate the c-jun promoter. Moreover, in addition to JNK, ERK5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements. Taken together, these results suggest that the pathway linking GPCRs to the c-jun promoter involves the integration of numerous signals transduced by a highly complex network of MAPK, rather than resulting from the stimulation of a single linear protein kinase cascade. Furthermore, our findings suggest that each signaling pathway affects one or more regulatory elements on the c-jun promoter and that the transcriptional response most likely results from the temporal integration of each of these biochemical routes.

Dataset Information

Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38? Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3.

Publications

Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38α Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3.

Similar Datasets

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