RNA Drug Discovery Effort Reveals 1 in 300 Million

Combining Inventions Allows Mass-Scale Scan of RNA-Targeting Compounds, Reveals a Hit Against an Elusive Breast Cancer Target

UF Scripps Biomedical Research scientist Matthew Disney, Ph.D. has found yet another groundbreaking approach to a problem that has long vexed scientists: How to cure diseases by targeting key RNA. Until now, RNA has been an elusive target for drug discovery. Discoveries made by Disney and his collaborators have rewritten that dogma.  

Matthew D. Disney, Ph.D. is professor and chair of the Department of Chemistry at UF Scripps Biomedical Research. Photo by Scott Wiseman.
Matthew D. Disney, Ph.D. is professor and chair of the Department of Chemistry at UF Scripps Biomedical Research. Photo by Scott Wiseman.

The group’s recent discoveries have important, broader implications for possibly treating many now-incurable diseases. For now, most drugs work by targeting proteins from humans or infectious organisms. Developing the ability to modulate RNA, as Disney’s inventions do, potentially increases the number of diseases that can be targeted with pharmaceuticals. 

By targeting RNA — the middleman between gene and protein — factors that cause disease never get built in the first place. Disney’s latest discovery capitalizes on work by his longtime collaborator, Brian Paegel, Ph.D., of the University of California, Irvine, to bring new efficiency to the drug-discovery process. Their approach makes it possible to screen hundreds of millions of drug-RNA interactions for effectiveness. The results were published recently in the Proceedings of the National Academy of Sciences.

The new findings were enabled by Paegel’s technique, which involves encoding small, drug-like molecules in DNA or using DNA-encoded “libraries” of compounds. These libraries allowed the researchers to use DNA sequencing to identify viable medicines that bind with RNA targets.

In recent proof-of-principle experiments involving triple-negative breast cancer RNA targets, Disney and his colleagues combined Paegel’s system with compounds discovered and built in Disney’s lab to screen hundreds of millions of drug-RNA interactions for effectiveness. Disney ultimately identified a highly potent inhibitor that stopped the cancer’s progression in preclinical models.

The findings show it is possible to substantially accelerate the drug discovery process. The technique opens new doors to treating diseases by targeting their RNA processes, said Disney, chair of the department of chemistry at UF Scripps.

Drug discovery is a time-consuming, tedious process. Scientists typically investigate one or a few targets at a time to determine if the respective drug and cell molecules bind correctly to treat disease. The new method leverages a simple-but-challenging concept: Every disease process is influenced by RNA. Targeting the right RNA with the right drug could represent a new route to a potential treatment or cure.

Disney and Paegel’s approach enables drug discovery to be done more quickly and on a massive scale. In the case of triple-negative breast cancer, it evaluated a library of more than 73,000 molecules, known as ligands, against some 4,000 RNA targets. In total, the screening parsed approximately 300 million interactions and ultimately identified numerous candidate drug-RNA pairs to target.

One of the newly discovered compounds potently and selectively inhibited the advance of triple-negative breast cancer by “reprogramming” genetic activity, the researchers found.

Triple-negative breast cancer accounts for only about 20% of all breast cancer cases but carries the highest mortality rate. It disproportionately affects younger and Black women in the United States, according to the American Cancer Society. Its name also belies its stubbornness: Triple-negative breast cancer cells lack crucial receptors that might otherwise allow hormonal and other treatments to work.

Disney likened the screening process to pulling a needle out of a 300 million-piece haystack.

“This is an RNA that is expressed in a type of breast cancer that is very hard to treat. When we delivered a compound that was identified by the screening, it stopped the cancer cell from having cancer-like behavior,” Disney said.

To establish their findings, Disney and his colleagues further studied three compounds identified by the screening. One of those compounds inhibited the cellular processing of miR-27a, a gene associated with triple-negative breast and other cancers. The compound significantly reduced gene expression activity in several cell lines, including prostate, cervical and two types of breast cancers.

More broadly, the researchers said the study is a compelling platform for evaluating new therapeutics meant to treat diseases by targeting RNA function. Disney said the screening process developed by his team mimics the evolution of complex molecular interaction networks that already exist in nature.

“We’re taking an evolutionary approach to find drugs that work well against really hard, challenging disease targets,” he said.

Next, Disney wants to develop the promising compound into a candidate that can be tested in human clinical trials. He also believes the same process used to screen and identify the compound can be put to broader use in biomedical research.

The work was funded by the National Institutes of Health, a Myotonic U.S. Fellowship research grant and the National Ataxia Foundation.

Media contact: Doug Bennett at dougbennett@ufl.edu or 352-265-9400