Discovery of protein arginine methyltransferase 1 inhibitor by structure-based pharmacophore modeling, virtual screening, molecular dynamics simulations, and the enhancement of paclitaxel's antitumor activity

  • Eur J Med Chem. 2025 Dec 5:299:118066. doi: 10.1016/j.ejmech.2025.118066.
Yan Su  1 ,  Wun-Taai Lok  2 ,  Mei-Mei Zhang  1 ,  Jian-Mei Gao  1 ,  Jiaxin He  1 ,  Nan Chao  1 ,  Hui Yuan  1 ,  Yifan Ouyang  3 ,  Zhou Hong  4 ,  Yanru Fan  1 ,  Dong Wang  5 ,  Yu Huang  6 ,  Hao Wang  7 ,  Hao Yang  8
Affiliations
  • 1. School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.
  • 2. Guangzhou International Campus, South China University of Technology, Guangzhou, 511442, China.
  • 3. Fujian Key Laboratory of Toxicant and Drug Toxicology, School of Medicine, Ningde Normal University, Ningde, Fujian, 352100, China.
  • 4. College of Life Science and Technology, Ningxia Polytechnic, Ningxia Open University, Yinchuan, 750021, China.
  • 5. College of Pharmaceutical Sciences and Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China. Electronic address: [email protected].
  • 6. School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China. Electronic address: [email protected].
  • 7. School of Pharmacy, Minzu University of China, Beijing, China. Electronic address: [email protected].
  • 8. School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China. Electronic address: [email protected].
PMID: 40834497 DOI: 10.1016/j.ejmech.2025.118066
Abstract

Protein arginine methyltransferase 1 (PRMT1), a key epigenetic regulator, is implicated in tumor progression and therapy resistance. Here, we identify a novel PRMT1 Inhibitor, YH-4, through structure-based pharmacophore modeling, virtual screening, and molecular dynamics simulations. YH-4 demonstrates potent PRMT1 inhibition (IC50 = 4.11 μM) and dose-dependently suppresses asymmetric dimethylarginine (ADMA) levels and histone H4R3me2a modification in triple-negative breast Cancer (TNBC) cells. In vitro, YH-4 induces cell cycle arrest, Apoptosis, and inhibits migration and colony formation in MDA-MB-231 cells. Notably, YH-4 synergizes with paclitaxel (PTX), reducing cell viability and enhancing PTX efficacy in a xenograft model in vivo. This study is the first to confirm that PRMT1 inhibitors act as chemotherapeutic sensitizers for paclitaxel in the treatment of TNBC. Molecular dynamics simulations confirm stable binding of YH-4 to PRMT1, driven by hydrogen bonding and hydrophobic interactions. This study highlights YH-4 as a promising therapeutic agent to overcome paclitaxel resistance in TNBC and provides a computational-experimental framework for developing PRMT1-targeted therapies.

Keywords
Chemotherapeutic sensitizers; PRMT1 inhibitor; Triple-negative breast cancer; Virtual screening.
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