<b>Abstract</b>:  A challenge in biomedical research is exploiting new targets for medicine development.  RNA directly causes many diseases and yet is believed to be recalcitrant to small molecule targeting.  Our programmatic focus has been on developing technologies to identify what cellular RNAs are “druggable” targets for small molecules and small molecules to target them.  In this talk, I will focus on the development of small molecules that target RNA structures and trigger their elimination or degradation from cells and pre-clinical animal models.  For example, structure-binding ligands have been endowed with the ability to affect degradation of repeat expansions to study molecular recognition of small molecules to RNA from cells to mouse models of disease by facilitating engagement of these toxic RNAs with RNA quality control machinery by using chimeric compounds that bind and RNA structure and recruit a ribonuclease to degrade it.  Mutant alleles that drive disease can be specifically targeted and eliminated by structure-binding compounds.  Small molecules can also facilitate natural decay of repeat expansions in other mechanistically distinct ways.  For example, in many disease settings intronic RNAs drive diseases and these intronic RNAs are not eliminated from cells but harbored as retained introns to protect them from degradation.   We have therefore designed monomeric degraders that affect RNA processing to liberate a retained intron causing natural elimination.  In each of these cases, cellular experiments have established modes of action as well as selectivity for these compounds that has included target engagement.  Furthermore, the cellular studies have been successfully translated to pre-clinical models of diseases that range from various cancers to ALS. These studies and others suggest that RNAs can be a rich source of small molecule targets and their biology can be programmably manipulated in many ways including targeted degradation.

Sequence-based design of small molecules targeting RNA structures

ACS Spring 2022

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