Development of a Selective Inhibitor of Protein Arginine Deiminase 2
| Autor: | Venkataraman Subramanian, Aaron Muth, Sangram S. Parelkar, Mitesh Nagar, Philip S. Kerry, Kathleen W. Clancy, Hema Srinath, Paul A. McEwan, Paul R. Thompson, Edward Beaumont |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Benzimidazole Hydrolases Isozyme Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Protein-Arginine Deiminase Type 2 Drug Discovery medicine Humans Potency Enzyme Inhibitors Protein-Arginine Deiminases HEK 293 cells Protein-arginine deiminase medicine.disease Molecular Docking Simulation HEK293 Cells 030104 developmental biology chemistry Biochemistry Drug Design 030220 oncology & carcinogenesis Rheumatoid arthritis Cancer research Molecular Medicine Benzimidazoles Function (biology) |
| Zdroj: | Journal of Medicinal Chemistry. 60:3198-3211 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Protein arginine deiminase 2 (PAD2) plays a key role in the onset and progression of multiple sclerosis, rheumatoid arthritis, and breast cancer. To date, no PAD2-selective inhibitor has been developed. Such a compound will be critical for elucidating the biological roles of this isozyme and may ultimately be useful for treating specific diseases in which PAD2 activity is dysregulated. To achieve this goal, we synthesized a series of benzimidazole-based derivatives of Cl-amidine, hypothesizing that this scaffold would allow access to a series of PAD2-selective inhibitors with enhanced cellular efficacy. Herein, we demonstrate that substitutions at both the N-terminus and C-terminus of Cl-amidine result in >100-fold increases in PAD2 potency and selectivity (30a, 41a, and 49a) as well as cellular efficacy (30a). Notably, these compounds use the far less reactive fluoroacetamidine warhead. In total, we predict that 30a will be a critical tool for understanding cellular PAD2 function and sets the stage for treating diseases in which PAD2 activity is dysregulated. |
| Databáze: | OpenAIRE |
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