Discovery of highly potent naphthalene/quinoline-based PAD inhibitors: Structure-activity relationship, selectivity, and cytotoxicity.

ABSTRACT: This study focuses on developing highly potent inhibitors targeting peptidyl arginine deiminases (PADs), particularly PAD4 and PAD1, which play critical roles in citrullination-linked diseases such as cancer and autoimmune disorders. A series of benzylamine- and benzimidazole-substituted compounds were synthesized and evaluated for their inhibitory activity. Key findings include the identification of naphthalene and quinoline-based scaffolds with hydroxyl substitutions, which exhibited superior inhibition of PAD1 and PAD4 (IC₅₀ values as low as 0.273 μM and 0.204 μM, respectively), compared with their precursor, Cl-amidine. While the most potent compounds 13 and 16 showed very low cytotoxicity (CC₅₀ > 80 μM), thus providing a wide therapeutic window. Structural modifi

SUBMITTER: Jia Y 

PROVIDER: S-EPMC12477756 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature