Cl-Amidine

Protein arginine deiminase 4 (PAD4) catalyzes the post-translational modification of arginine residues on histones to form citrulline, which plays a large role in regulating gene expression. Dysregulated PAD4 activity has been implicated in cancer and rheumatoid arthritis. Cl-amidine is an inhibitor of PAD4 deimination activity with an IC50 value of 5.9 μM in an in vitro activity assay. It irreversibly inactivates (kinact/KI = 13,000 M-1min-1) PAD4 by covalently modifying an active site cysteine that is important for its catalytic activity. Cl-amidine also inhibits PAD1 and PAD3 with IC50 values of 0.8 and 6.2 μM, respectively. Cl-amidine is cytotoxic to HL-60, MCF7, and HT-29 cancer cell lines (IC50s = 0.25, 0.05 and 1 μM, respectively). In a CIA mouse model of inflammatory arthritis, Cl-amidine dose dependently decreases the citrulline content in serum and joints and reduces the development of IgG autoantibodies.