A Bifunctional Small Molecule Degrader of the Long Noncoding RNA MALAT1 Triplex.

Abstract

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.