Modular RNA-based PROTACs for selective degradation of multidomain RNA-binding proteins

RNA-binding proteins (RBPs) are central regulators of gene expression, yet their modular and dynamic architectures have hindered efforts to pharmacologically target them. The splicing factor RNA Binding Motif 39 (RBM39) is an attractive anti-cancer target, currently addressed by aryl sulfonamides that act as molecular glues to promote DCAF15-dependent degradation. However, their clinical efficacy is contingent on DCAF15 expression. Here, we report a modular RNA-based PROTAC strategy for DCAF15-independent, selective depletion of RBM39. Guided by the tandem organization of the RBM39 RNA recognition motifs (RRM1 and RRM2), we engineered a high-affinity RNA aptamer that simultaneously engages both domains. Biophysical and structural analyses revealed the relative arrangement of both RRMs required for multivalent binding. Conjugation of this aptamer to the cereblon ligand pomalidomide enabled proteasomal degradation of RBM39 in colorectal cancer cells. The resulting RNA-PROTAC induced dose-dependent RBM39 degradation, impaired splicing function, and suppressed cancer cell proliferation, while unconjugated aptamer or free pomalidomide had only a limited effect. These findings establish RNA-guided PROTACs as programmable tools to selectively degrade multidomain RBPs, extending targeted protein degradation beyond the scope of conventional small molecules and providing a new framework for therapeutic intervention in RBP-driven diseases.