Development of a Selective Inhibitor of Protein Arginine Deiminase 2.

Abstract

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.

• Authors: Aaron Muth, Venkataraman Subramanian, Edward Beaumont, Mitesh Nagar, Philip Kerry, Paul McEwan, Hema Srinath, Kathleen Clancy, Sangram Parelkar, Paul R Thompson
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 60 Issue 7 Pg. 3198-3211 (04 13 2017) ISSN: 1520-4804 [Electronic] United States
• PMID: 28328217 (Publication Type: Journal Article)

Chemical References

• Benzimidazoles
• Enzyme Inhibitors
• benzimidazole
• Hydrolases
• PADI2 protein, human
• Protein-Arginine Deiminase Type 2
• Protein-Arginine Deiminases

Topics

• Benzimidazoles (chemistry, pharmacology)
• Drug Design
• Enzyme Inhibitors (chemistry, pharmacology)
• HEK293 Cells
• Humans
• Hydrolases (antagonists & inhibitors, metabolism)
• Molecular Docking Simulation
• Protein-Arginine Deiminase Type 2
• Protein-Arginine Deiminases