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  3. Discovery and biological evaluation of potent 2-trifluoromethyl acrylamide warhead-containing inhibitors of protein disulfide isomerase

Discovery and biological evaluation of potent 2-trifluoromethyl acrylamide warhead-containing inhibitors of protein disulfide isomerase

  • Eur J Med Chem. 2025 Feb 5:283:117169. doi: 10.1016/j.ejmech.2024.117169.
Jung-Chun Chu 1,  Keng-Chang Tsai 2,  Ting-Yu Wang 3,  Tzu-Yin Chen 4,  Ju-Ying Tsai 3,  Tien Lee 3,  Mei-Hsiang Lin 4,  Yves S Y Hsieh 5,  Chin-Chung Wu 6,  Wei-Jan Huang 7
Affiliations

Affiliations

  • 1 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 2 National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan; Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 3 Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 4 School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 5 Division of Glycoscience, Department of Chemistry, School of Engineering Sciences in Chemistry, Biotechnology and Health, Royal Institute of Technology (KTH), AlbaNova University Centre, Stockholm, SE-10691, Sweden.
  • 6 Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: ccwu@kmu.edu.tw.
  • 7 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; School of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address: wjhuang@tmu.edu.tw.
PMID: 39708767 DOI: 10.1016/j.ejmech.2024.117169
Abstract

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.

Keywords

2-Trifluoromethyl acrylamide; Protein disulfide isomerases; Thrombosis; Warhead.

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