Abstract 5790: Next-generation PRMT5 activity modulation through directed degradation

Abstract PRMT5 is a key epigenetic regulator that is responsible for symmetric demethylation (SDMA) of arginine residues on histones and non-histone proteins, leading to regulation of transcription, RNA splicing, and genome stability. PRMT5 activity is linked to a range of malignancies, making it an attractive therapeutic target. The therapeutic potential of SAM and protein substrate competitive PRMT5 inhibitors have been hampered by dose-limiting cytopenia leading to incomplete target coverage. In contrast, MTA-cooperative inhibitors exploit the accumulation of MTA, a SAM-competitive inhibitor of PRMT5, in MTAP-deleted tumors to achieve enhanced tumor selectivity. MTA-cooperative degraders offer the potential to eliminate both catalytic and non-catalytic functions of PRMT5 with improved depth and durability of target modulation. Here, we describe PRMT5-directed degraders that rapidly, potently, and selectively eliminate PRMT5. Our degraders exhibit potent and robust PRMT5 degradation within 6 hours of treatment, leading to marked suppression of SDMA. Mechanistic studies demonstrate that PRMT5 loss is strictly dependent on UPS, as pharmacological blockade of ubiquitination or proteasomal activity effectively abrogates degrader-induced PRMT5 turnover. Our data highlights the potential for PRMT5 targeted degradation, driving a rapid and selective silencing of PRMT5 activity that can overcome limitations of first-generation inhibitors and provide a differentiated therapeutic approach for PRMT5-driven cancers. Citation Format: Jose C. Clemente, Xuqing Zhang, Brian Vidal, Aaron Stonberger, Sudeep Banjade, Cory T. Rice, Nathan M. Kendsersky, Curran A. Rhodes, Matthew Tudor, Qiaolin Deng, Bomie Han, Clemente Aguilar-Bonavides, Elham Behshad, Steven D. Knight, Corey Strickland, Larry J. Jolivette, Ryan G. Kruger, . Next-generation PRMT5 activity modulation through directed degradation [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 5790.