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.