The targeted degradation of RNA, particularly long noncoding RNAs (lncRNAs), holds immense potential for therapeutic interventions in diseases associated with aberrant RNA regulation. Here, we introduce a novel Proximity-Induced Nucleic Acid Degrader (PINAD-1), a first-in-class small molecule that selectively induces the degradation of MALAT1, a lncRNA implicated in the regulation of metastatic processes. PINAD-1 is designed by conjugating a binder specific for the triple helix structure of MALAT1 to an imidazole-based RNA-degrading warhead, enabling specific cleavage of the MALAT1 transcript in vitro and in cellulo, with minimal off-target effects on the structurally similar NEAT1 lncRNA. Through mechanistic studies, we show that effective RNA degradation is not solely dependent on proximity but requires a precise structural context, as demonstrated by the differential activity of PINAD-1 compared to the structurally analogous but functionally inert conjugate PINAD-2. Our findings underscore the importance of binder-induced destabilization and RNA geometry in facilitating RNA degradation. This work lays the foundation for the design of bifunctional small-molecule RNA degraders as powerful tools for the modulation of structured noncoding RNAs, offering potential applications in RNA-based therapeutics.
Bernardes et al. (Wed,) studied this question.