Unique Cysteine-Directed Covalent Inhibition of PRMT1 Suppresses Breast Tumorigenesis

  • J Med Chem. 2026 Jul 9;69(13):15423-15457. doi: 10.1021/acs.jmedchem.6c00262.
Min Shao  1 ,  Ruining Li  1 ,  Jinglei Hu  1 ,  Wenjie Xi  1 ,  Raghupathi Mutyala  1 ,  Lulu Guan  2 ,  Chaoqun Huang  3 ,  Renhong Sun  4 ,  Xiaobao Yang  4 ,  Bo Jin  1 ,  Bo Zhao  1 ,  Erjun Hao  2 ,  Zhimin Zhang  5 ,  Lin Li  1 ,  Xufen Yu  3 ,  Mingyan Zhu  1 ,  Yudao Shen  1  6
Affiliations
  • 1. Shanghai Frontiers Science Center of Targeted Drugs, State Key Laboratory of Innovative Immunotherapy, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Engineering Research Center of Cell & Therapeutic Antibody Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2. Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs, School of Pharmaceutical Sciences, Henan Normal University, Xinxiang 453007, China.
  • 3. School of Pharmaceutical Sciences, Key Laboratory of Smart Drug Delivery (Ministry of Education), MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Fudan University, Shanghai 201203, China.
  • 4. Gluetacs Therapeutics (Shanghai) Co., Ltd., Shanghai 201306, China.
  • 5. State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, School of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 6. Central Research Institute, State Key Laboratory of Innovative Immunotherapy Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai 201203, China.
PMID: 42309962 DOI: 10.1021/acs.jmedchem.6c00262
Abstract

Dysregulation of PRMT1, a key epigenetic enzyme, is strongly implicated in breast Cancer pathogenesis. However, developing selective PRMT1 inhibitors has been challenging due to the high conservation of the catalytic domain across PRMT family members. We herein report 17zh (MS3-123), the first small-molecule, nanomolar covalent inhibitor targeting the unique Cys119 within the SAM-binding pocket of PRMT1 (IC50 = 11.4 nM) with over 17-96-fold selectivity against Other type I PRMTs subfamily and >439-fold selectivity against type II PRMT5. 17zh selectively engages Cys119, inhibiting PRMT1 activity at both enzymatic and cellular levels. Functionally, 17zh suppressed breast Cancer cell proliferation, migration, invasion, induced cell cycle arrest and Apoptosis, and impaired tumor growth in vivo in the MDA-MB-231-xenograft model. Our findings establish 17zh as both a valuable chemical probe for PRMT1 research and a promising lead candidate for breast Cancer treatment, highlighting the potential of covalent targeting for selective epigenetic drug discovery.

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