Category: Drug Target Strategies

1366-B - RNA as a small molecule drug target: Discovery of selective RNA-binding small molecules by high-throughput affinity-selection mass spectrometry

Monday, February 5, 2018
5:00 PM - 6:00 PM

Approximately 60% of DNA is transcribed as RNA, but only 1-2% codes for proteins. There is evidence that the remaining non-coding RNA (ncRNA) is involved in the regulation or execution of cellular processes, and has been genetically linked to human diseases and traits in similar numbers as the protein-coding genes. Understanding the function of ncRNA and its interactions with small molecules will likely open up new therapeutic approaches for various diseases.

To study ncRNA as a small molecule druggable target, we first investigated the use of the Automated Ligand Identification System (ALIS). ALIS is an affinity-selection MS platform capable of high-throughput screening for small-molecule binding, and has been routinely used to detect thousands of protein-small molecule interactions. We successfully adapted ALIS for detection of RNA-small molecule interactions with regulatory ncRNA bacterial riboswitches and known small molecule drug leads, and used ALIS to characterize these RNA-ligand binding events. We next identified over 40 ncRNA from a range of classes and disease areas. These ncRNA targets were screened in ALIS against chemically diverse small molecule libraries, functionally annotated libraries from phenotypic screens, and libraries enriched in RNA-binding properties (60,000+ compounds total). We have generated millions of screening data points from which we have identified new drug-like small molecules that bind to ncRNA. By further studying the structural conformation and functional consequences, we are revealing new mechanisms involving small molecule-ncRNA interactions. Here, we outline our results and discuss their implications for small-molecule drug discovery efforts.

Noreen Rizvi

Senior Biochemist
Siemens Healthineers
New York, NY

Noreen Rizvi received her B.S. in Chemical Engineering from Cornell University. After a quick stint teaching chemistry at Weill Cornell Medical College in Doha, Qatar, Noreen went on to earn her Ph.D. in Chemical Engineering at Northeastern University where she worked on enhancing the production of valuable anticancer compounds through genetic engineering of plant cell cultures. Noreen did her postdoctoral training at Merck Research Labs where she investigated the druggability of disease-relevant RNA by small molecule drugs. Currently, Noreen is a Senior Biochemist at Siemens Healthineers, where she is developing diagnostic assays for clinical applications.