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.