Small Molecule RNA Degraders

Abstract RNA is a central molecule in life, involved in a plethora of biological processes and playing a key role in many diseases. Targeting RNA emerges as a significant endeavor in drug discovery, diverging from conventional protein‐centric approaches to tackle various pathologies. Whilst identifying small molecules that bind to specific RNA regions is the first step, the abundance of non‐functional RNA segments renders many interactions biologically inert. Consequently, small molecule binding does not necessarily meet stringent criteria for clinical translation, calling for solutions to push the field forward. Converting RNA‐binders into RNA‐degraders presents a promising avenue to enhance RNA‐targeting. This mini‐review outlines strategies and exemplars wherein simple small molecule RNA binders are reprogrammed into active degraders through the linkage of functional groups. These approaches encompass mechanisms that induce degradation via endogenous enzymes, termed RIBOTACs, as well as those with functional moieties acting autonomously to degrade RNA. Through this exploration, we aim to offer insights into advancing RNA‐targeted therapeutic strategies.