The rapid emergence of small molecule RNA modulator hit discovery: unlocking the potential.

INTRODUCTION

RNA is now recognized as an active regulatory target rather than a passive intermediary, expanding therapeutic opportunities beyond protein-centric drug discovery. Small-molecule RNA modulators offer access to novel target space and new mechanisms to modulate protein targets that are difficult to drug directly, but clinical translation remains limited.

AREAS COVERED: This review examines the principal challenges and opportunities in small-molecule RNA-targeted hit discovery: target prioritization based on genetics, structure, and function; mechanisms of modulation beyond splicing, including translation interference and targeted RNA degradation; the persistent gap between RNA structural engagement and functional outcome; hit-finding strategies; and hit-to-lead optimization. Here, the authors discuss how limitations do not lie solely in identifying RNA binders, but in predicting prospectively whether binding to a defined RNA structure will produce a functional consequence.

EXPERT OPINION: Progress requires closing the structure-function-druggability loop through in-cell validation and RNA-specific druggability models, deploying targeted RNA degradation to convert silent binders into functional molecules, establishing standardized validation cascades and translational PK/PD frameworks, building RNA-native chemical infrastructure, and training AI on RNA-specific datasets. Pre-competitive infrastructure to generate shared structural and functional data will accelerate the field.