Targeting RNA with Druglike Small Molecules

The identification of selective RNA- and DNA-binding small molecules has been a longstanding challenge for chemical biology. Recent studies have demonstrated that while more than 85% of the human genome is transcribed into RNA, just 3% of those transcripts code for protein sequences.  Coupled with the discovery that non-coding functions of RNA can drive disease, RNA has emerged as an intriguing but challenging therapeutic target for small molecules. In particular, regulatory nucleic acids that drive the expression of clinically important but so-called "undruggable" proteins such as c-MYC and KRAS respresent targets of interest.  Our laboratory aims to advance the field of targeting RNA with druglike small molecules on multiple fronts.  We use an integrated approach, including chemical biology, medicinal chemistry, structural biology, and functional genomics to understand and control RNA targets with small molecules. WIth respect to discovery, we have developed a small molecule microarray (SMM) high throughput screening platform that allows us to rapidly identify and profile the RNA-binding properties of small molecules.  We use hits from this screening platform as the basis for development of small molecule probes that selectively target RNA. This work has led to the discovery that druglike compounds are suitable starting points for inhibitor discovery efforts for RNA targets, while driving fundamental advances in understanding RNA-small molecule recognition.  Together, this work aims to develop RNA-binding small molecule probes to improve our understanding of RNA-mediated processes and disease states, particularly for cancers with no existing treatment options.