Development of a Selective Inhibitor of Protein Arginine Deiminase 2.
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.
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , 364 Plantation Street, Worcester, Massachusetts 01605, United States.|Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University , Queens, New York 11439, United States.
Aaron
A
Muth
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , 364 Plantation Street, Worcester, Massachusetts 01605, United States.
Venkataraman
V
Subramanian
Evotec , Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
Edward
E
Beaumont
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , 364 Plantation Street, Worcester, Massachusetts 01605, United States.
Mitesh
M
Nagar
Evotec , Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
Philip
P
Kerry
Evotec , Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
Paul
P
McEwan
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , 364 Plantation Street, Worcester, Massachusetts 01605, United States.
Hema
H
Srinath
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , 364 Plantation Street, Worcester, Massachusetts 01605, United States.
Kathleen
K
Clancy
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , 364 Plantation Street, Worcester, Massachusetts 01605, United States.
Sangram
S
Parelkar
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , 364 Plantation Street, Worcester, Massachusetts 01605, United States.|Program in Chemical Biology, University of Massachusetts Medical School , 364 Plantation Street, Worcester, Massachusetts 01605, United States.
Paul R
0000-0002-1621-3372
PR
Thompson
D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; C031000:benzimidazole; D006867:Hydrolases; C000620352:PADI2 protein, human; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases