RNAs are molecules copied from DNA and used by the cell to make proteins, which are structural building blocks of the cell. However, thousands of cellular RNAs are not just intermediates for protein production but rather function on their own as key regulators of diverse biological phenomena. Because an increasing number of RNAs is linked to human pathologies including incurable neurodegenerative diseases, antibiotic resistance, and human diseases caused by RNA viruses (i.e. SARS, HIV, Ebola, influenza, hepatitis C, Zika, etc.), RNA molecules represent an untapped source of therapeutic targets. Furthermore, given recent discoveries that not only proteins but also RNAs are druggable, there is currently a major push to find bioavailable inhibitors that target specific RNAs.
While a few bioavailable small molecules have been recently successfully applied to target RNA, finding specific RNA inhibitors remains challenging, because lead compounds cannot be easily rationally designed from RNA sequence or structure. One promising strategy for RNA drug discovery is to target specific RNA elements that are stabilized by protein binding. However, the unbiased identification of small molecules that selectively target RNA-protein interactions remains unachieved due to the lack of technology to quickly and easily reveal and measure, in an unbiased manner, targeted RNA-protein interaction in cells. Within the context of our ERC starting grant project, we developed a powerful technology, termed “incPRINT,” capable of identifying for the first time in a highthroughput, quantitative and unbiased manner, RNA-protein interactions. With this project, we adapted our incPRINT technology to a proof-of-principle demonstration of its utility for drug discovery. We applied our technology to an RNA-protein interaction that plays a key role in human acute myeloid leukemia (AML), one of the most common leukemias in adults, and identified a family of molecules that target this interaction. Morevover, using our technology we are able to shed light on the mechanisms of action of these drugs, thus enabling their eventual optimization. Taken together, we demonstrated that incPRINT technology is the first platform capable of being harnessed as an in-cell drug screening targeting specific RNA-protein interactions and has a potential to breakthrough implications in RNA drug discovery for fundamental research, applied research, pharma and biotech companies. This proof-of-concept demonstration has laid the groundwork for the future creation of a start-up for the further development of this powerful technology.
