Synthesis and Biological Evaluation of 3-Arylindazoles as Selective MEK4 Inhibitors
| Autor: | Raymond C. Bergan, Mariam Donny George, Karl A. Scheidt, Purav P. Vagadia, Gary E. Schiltz, Matthew R. Clutter, Ryan R. Gordon, Graham Fowler, Kristine K. Deibler, Rama K. Mishra, Matthew S. O'Connor |
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| Rok vydání: | 2019 |
| Předmět: |
Indazoles
Molecular model MAP Kinase Kinase 4 p38 mitogen-activated protein kinases Drug Evaluation Preclinical Biochemistry Article Metastasis Substrate Specificity Prostate cancer Prostate Drug Discovery medicine Humans General Pharmacology Toxicology and Pharmaceutics Protein kinase A Protein Kinase Inhibitors Pharmacology Chemistry Kinase Organic Chemistry medicine.disease medicine.anatomical_structure Cancer research Molecular Medicine Phosphorylation |
| Zdroj: | ChemMedChem. 14(6) |
| ISSN: | 1860-7187 |
| Popis: | Herein we report the discovery of a novel series of highly potent and selective mitogen-activated protein kinase kinase 4 (MEK4) inhibitors. MEK4 is an upstream kinase in MAPK signalling pathways that phosphorylates p38 MAPK and JNK in response to mitogenic and cellular stress queues. MEK4 is overexpressed and induces metastasis in advanced prostate cancer lesions. However, the value of MEK4 as an oncology target has not been pharmacologically validated because selective chemical probes targeting MEK4 have not been developed. Optimization of this series via structure activity relationships and molecular modelling led to the identification of compound 6ff (4-(6-fluoro-2H-indazol-3-yl)benzoic acid), a highly potent and selective MEK4 inhibitor. This series of inhibitors is the first of its kind in both activity and selectivity and will be useful in further defining the role of MEK4 in prostate and other cancers. |
| Databáze: | OpenAIRE |
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