Unique Cysteine-Directed Covalent Inhibition of PRMT1 Suppresses Breast Tumorigenesis

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 (IC 50 = 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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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2026-06-17
DOI
https://doi.org/10.1021/acs.jmedchem.6c00262
Primary Topic
Cancer-related gene regulation
Type
article
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article

Unique Cysteine-Directed Covalent Inhibition of PRMT1 Suppresses Breast Tumorigenesis

Er‐Jun Hao, Mingyan Zhu, Min Shao, Wenjie Xi et al.
Journal of Medicinal Chemistry
Cancer-related gene regulation
article

Unique Cysteine-Directed Covalent Inhibition of PRMT1 Suppresses Breast Tumorigenesis

Er‐Jun Hao, Mingyan Zhu, Min Shao, Wenjie Xi, 靳博, Xiaobao Yang, Renhong Sun, Xufen Yu, Bo Zhao, Raghupathi Mutyala, Lulu Guan, Zhimin Zhang, Lin Li, Ruining Li, Yudao Shen, J B Hu, Chaoqun Huang
article en

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 (IC 50 = 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.

Journal of Medicinal Chemistry
China Pharmaceutical University (CN), Shanghai Jiao Tong University (CN), Fudan University (CN), Technology Holding (United States) (US), NuVue Therapeutics (United States) (US), Central Research Institute (IN), Ministry of Education (KR), Ministry of Education (TH), Henan Normal University (CN)
Good health and well-being
Openalex Percentile: Top 13%
Cancer-related gene regulation
DOISourceOpenAlex
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