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Synthesis and Biological Evaluation of 3-Arylindazoles as Selective MEK4 Inhibitors |
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| Authors: | Kristine K. Deibler Dr. Gary E. Schiltz Dr. Matthew R. Clutter Dr. Rama K. Mishra Purav P. Vagadia Dr. Matthew O'Connor Mariam Donny George Dr. Ryan Gordon Graham Fowler Dr. Raymond Bergan Prof. Karl A. Scheidt |
| Affiliation: | 1. Department of Chemistry, Northwestern University, Evanston, IL, 60208 USA;2. Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL, 60208 USA Department of Pharmacology, Northwestern University, Chicago, IL, 60611 USA Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611 USA;3. Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611 USA Chemistry of Life Process Institute, Northwestern University, Evanston, IL, 60208 USA Department of Molecular Biosciences, Northwestern University, Evanston, IL, 60208 USA;4. Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL, 60208 USA Department of Pharmacology, Northwestern University, Chicago, IL, 60611 USA;5. Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL, 60208 USA;6. Chemistry of Life Process Institute, Northwestern University, Evanston, IL, 60208 USA;7. Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239 USA |
| Abstract: | 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 signaling 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 modeling led to the identification of compound 6 ff (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. |
| Keywords: | antitumor agents indazoles MEK4 kinases prostate cancer |