Pre-mRNA splicing modulation

Abstract

Pre-mRNA alternative splicing occupies a central role in the determination of protein expression and identity. Therefore, modulation of this process by small molecules offers an attractive development strategy to drug classically intractable diseases, particularly those linked etiologically to protein targets considered conventionally "undruggable." The first and most successful clinical example to date is Evrysdi® (risdiplam) - approved in 2020 for the treatment of spinomuscular atrophy (SMA). Although no other small molecules have yet achieved FDA-approved status, the last five years have witnessed a surge of small molecule splicing modulators entering first-in-human clinical trials. However, the pharmacological mechanisms through which these compounds influence splicing are diverse and accompanied by unique challenges. This chapter recounts the antecedents of modern pre-mRNA splicing modulation by small molecules, surveys the many known leverageable points of intervention, and discusses drug discovery considerations special to each.