Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is caused by the aberrant alternative pre-mRNA splicing of microtubule-associated protein tau ( MAPT ) exon 10, the inclusio...

RNA presents abundant opportunities as a drug target, offering significant potential for small molecule medicine development. The transcriptome, comprising both coding and noncoding RNAs, is a rich area for therapeutic innovation, yet challenges persist in targeting RNA with small molecules. RNA structure can be predicted with or without experimental data, but discrepancies with the actual biological structure can impede progress. Prioritizing RNA targets supported by genetic or evolutionary evidence enhances success. Further, small molecules must demonstrate binding to RNA in cells, not solely in vitro, to validate both the target and compound. Effective small molecule binders modulate functional sites that influence RNA biology, as binding to nonfunctional sites requires recruiting effector mechanisms, for example degradation, to achieve therapeutic outcomes. Addressing these challenges is critical to unlocking RNA’s vast potential for small molecule medicines, and a strategic framework is proposed to navigate this promising field, with a focus on targeting human RNAs.