Development of a Selective Inhibitor of Protein Arginine Deiminase 2.
Thompson Lab; Department of Biochemistry and Molecular Pharmacology; Program in Chemical Biology
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry
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.
Benzimidazoles, Drug Design, Enzyme Inhibitors, HEK293 Cells, Humans, Hydrolases, Molecular Docking Simulation, Protein-Arginine Deiminases
DOI of Published Version
J Med Chem. 2017 Apr 13;60(7):3198-3211. doi: 10.1021/acs.jmedchem.7b00274. Epub 2017 Mar 31. Link to article on publisher's website
Journal of medicinal chemistry
Muth A, Subramanian V, Beaumont E, Nagar M, Kerry P, McEwan P, Srinath H, Clancy KW, Parelkar S, Thompson PR. (2017). Development of a Selective Inhibitor of Protein Arginine Deiminase 2.. University of Massachusetts Medical School Publications. https://doi.org/10.1021/acs.jmedchem.7b00274. Retrieved from https://escholarship.umassmed.edu/publications/5