Jung-Chun Chu, Keng-Chang Tsai, Ting-Yu Wang, Tzu-Yin Chen, Ju-Ying Tsai, Tien Lee, Mei-Hsiang Lin, Yves S.Y. Hsieh, Chin-Chung Wu, Wei-Jan Huang,
European Journal of Medicinal Chemistry, 283, 2025, 117169
https://doi.org/10.1016/j.ejmech.2024.117169
Protein disulfide isomerase (PDI) regulates multiple protein functions by catalyzing the oxidation, reduction, and isomerization of disulfide bonds. The enzyme is considered a potential target for treating thrombosis. We previously developed a potent PDI inhibitor, CPD, which contains the propiolamide as a warhead targeting cysteine residue in PDI. To address its issues with undesirable off-target effects and weak metabolic stability, we replaced the propiolamide group with various electrophiles. Among these, compound 2d, which contains 2-trifluoromethyl acrylamide exhibited potent PDI inhibition compared to the reference PACMA31. Further structural optimization of compound 2d led to a novel series of 2-trifluoromethyl acrylamide derivatives. Several of these compounds displayed substantially improved enzyme inhibition. Notably, compound 14d demonstrated the strongest inhibition against PDI, with an IC50 value of 0.48 ± 0.004 μM. Additionally, compound 14d was found to exhibit a reversible binding mode with PDI enzyme. Further biological evaluations show that 14d suppressed platelet aggregation and thrombus formation by attenuating GPIIb/IIIa activation without significantly causing cytotoxicity. Altogether, these findings suggest PDI inhibitors could be a potential strategy for anti-thrombosis.
