Abstract 4609: Discovery and development of PRMT5/MEP50 degraders for the selective targeting of MTAP-null cancers

Abstract Protein arginine methyltransferase 5 (PRMT5) is an important regulator of various biological processes through the mono- and symmetric dimethylation of protein substrates. PRMT5 is overexpressed in multiple human cancers, and its overexpression is often associated with poor prognosis. We recently reported MS115, a best-in-class PRMT5 degrader that potently and selectively degraded PRMT5 and its coactivator, MEP50, in concentration-, time-, and ubiquitin-proteasome system-dependent manners. MS115 displayed markedly improved PRMT5/MEP50 degradation potency over published PRMT5 degraders, which translated to superior antiproliferative effect in both breast and prostate cancer cells. More importantly, MS115 exhibited safer cytotoxicity profile compared to existing PRMT5 degraders and inhibitors in normal cells. Nonetheless, residual antiproliferative activity in MTAP-proficient cells highlights the need for improved therapeutic selectivity. To address this limitation, we tackled the synthetic lethality between PRMT5 and MTAP loss. MTAP homozygous deletions, present in approximately 15% of human cancers, lead to accumulation of methylthioadenosine (MTA), an endogenous PRMT5 inhibitor. By leveraging MTA-cooperative PRMT5 inhibitors, we generated a series of PRMT5/MEP50 degraders that selectively degraded PRMT5 and MEP50 and suppressed proliferation in MTAP-null cancer cells, while sparing MTAP-wild-type counterparts across breast cancer and cholangiocarcinoma models. This targeted selectivity enables the study of both catalytic and non-catalytic functions of PRMT5 with substantially improved tolerability. Collectively, we have discovered MS115 and multiple MTA-cooperative PRMT5/MEP50 degraders with enhanced potency and safety, providing valuable chemical probes and promising candidates for the treatment of cancers driven by PRMT5 dysregulation. Citation Format: Yue Zhong, Qian Chao, Yan Xiong, Husnu Kaniskan, Jian Jin, . Discovery and development of PRMT5/MEP50 degraders for the selective targeting of MTAP-null cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4609.