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

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

  • Eur J Med Chem. 2025 May 29:296:117830. doi: 10.1016/j.ejmech.2025.117830.
Yijiang Jia 1,  Sina Bahraminejad 2,  Xin Duan 3,  Sydney Kong 4,  Ayijiang Taledaohan 5,  Chenyao Jiang 2,  Dejian Ma 2,  Jianxiong Jiang 2,  Yuji Wang 6,  Jiawang Liu 7
Affiliations

Affiliations

  • 1 Medicinal Chemistry Core, Office of Research, University of Tennessee Health Science Center, Memphis, TN, 38163, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
  • 3 Department of Neurology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan.
  • 4 College of Arts and Sciences, Vanderbilt University, Nashville, TN, 37240, USA.
  • 5 Department of Medicinal Chemistry, School of Pharmaceutical Sciences of Capital Medical University, 10 Xi Tou Tiao, You an Men, Beijing, 100069, PR China; Department of Medicinal Chemistry, Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Beijing Laboratory of Biomedical Materials, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, 10 Xi Tou Tiao, You an Men, Beijing, 100069, PR China.
  • 6 Department of Medicinal Chemistry, School of Pharmaceutical Sciences of Capital Medical University, 10 Xi Tou Tiao, You an Men, Beijing, 100069, PR China; Department of Medicinal Chemistry, Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Beijing Laboratory of Biomedical Materials, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, 10 Xi Tou Tiao, You an Men, Beijing, 100069, PR China. Electronic address: wangyuji@ccmu.edu.cn.
  • 7 Medicinal Chemistry Core, Office of Research, University of Tennessee Health Science Center, Memphis, TN, 38163, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. Electronic address: jliu90@uthsc.edu.
PMID: 40479895 DOI: 10.1016/j.ejmech.2025.117830
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 modifications provided valuable insights into structure-activity relationships and strategies for activity optimization. The hydroxy-naphthalene scaffold of 13 and 16 revealed a previously unrecognized binding site (Glu575) on the PAD4 enzyme, which was visualized through docking simulations. These inhibitors serve as valuable tools for investigating PAD functions and exploring potential therapeutic applications.

Keywords

Citrullination; Enzyme inhibition; Naphthalene scaffold; PAD inhibitor; Structure-activity relationship.

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