Next-generation PRMT5 activity modulation through directed degradation

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.