RNA directly causes many diseases and yet is believed to be recalcitrant to small molecule targeting. We have been developing technologies to identify what cellular RNAs are “druggable” targets for small molecules and small molecules that target RNA structures. These compounds affect RNA biology in varied ways and can be designed from RNA sequence. In this talk we will describe chimeric compounds that bind RNA targets that are coupled to a second compound that binds to and locally recruites RNase L. This causes the catalytic and substoichiomeric degradation of RNA targets to which the compounds bind. We will describe new advances in this area that include platform advances to identify new ribonucleases that can be recruited and methods to facilitate the identification of small molecules that can recruit them to RNA targets. These approaches will be exemplified with RNA degraders to target and eliminate a toxic RNA that causes the most common form of familial als and ftd. These degraders cause allele specific elimination of the toxic RNA in a variety of cell lines, resulting in board and specific improvements of disease defects. Additionally, the molecules cause the elimination of the toxic RNA in the brains of two different mouse models of disease. These studies support the assertion that RNAs can be a rich source of small molecule medicine targets and their biology can by affected by targeted degradation.

Development and optimization of small molecule RNA degraders

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.