Despite the scientific advancements made in creating medicines that can target and treat diseases, researchers still face the challenge of targeting “undruggable” targets. Most drugs target proteins to treat diseases, however, there are some proteins that conventional drugs cannot access for reasons such as a protein molecule’s shape or how it folds. There have been many strategies and tools developed to overcome these challenges such as targeting RNA. RNAs have not been viewed as drug targets as of recent due to their short-lived existence, changeable shape, and limited array of building blocks. Now, researchers at Scripps Research report they have developed a new RNA drug discovery tool that allows rapid drug discovery and optimization of RNA-targeting compounds.

Their new tool and approach are described in a paper titled, “A general fragment-based approach to identify and optimize bioactive ligands targeting RNA,” and published in the journal Proceedings of the National Academy of Sciences.

“RNAs have important functions that are dictated by their structure,” the investigators wrote. “Indeed, small molecules that interact with RNA structures can perturb function, serving as chemical probes and lead medicines. Here we describe the development of a fragment-based approach to discover and optimize bioactive small molecules targeting RNA.”

The new tool is called Chem-CLIP-Fragment Mapping. “It allows us to tackle very hard molecular recognition problems to enable us to make lead medicines across multiple indications,” said Matthew Disney, PhD, a chemist at Scripps Research, Florida. “This opens great potential to redefine what’s truly ‘undruggable.'”

The new system adapts a recent advance in protein-targeting drug discovery which uses weak binding, drug-like chemical fragments to reveal potential templates.

Here, the fragments are “functionalized,” or appended with tags and light-sensitive modules, allowing them to be seen and identified. The original protein-targeting drug discovery strategy was developed by Christopher Parker, PhD, as a postdoctoral fellow in the lab of Scripps Research biochemist Benjamin Cravatt, PhD.

Scripps Research Chemist Matthew Disney, PhD, and graduate student Blessy Suresh in their Jupiter, FL, lab. [Scripps Research]

“This is what Scripps Research is, we develop tools,” said Parker, now an assistant professor at Scripps Research, Florida. “Our collaborative environment allows us to do this.”

The Chem-CLIP-Frag-Map system helps reveal multiple opportunities to bind, and which allows them to modify the RNA targets. The researchers say the system aids scientists in engineering and optimizing potential medicines to bind more tightly, be more specific, and less likely to have off-target side-effects.

“These two things bind cooperatively, and so the whole is better than the parts,” Disney said.

The Scripps Researchers used their new tool to find compounds for microRNA-21, a key RNA involved in triple-negative breast cancer. Triple-negative breast cancer is an aggressive breast cancer subtype, with no clinically approved targeted therapies. The Chem-CLIP-Frag-Map tool uses a light-sensitive module called a diazirine group that covalently crosslinks to RNA with exposure to UV light.

“The system helped us optimize the fragments to design bioactive complexes with higher selectivity and potency as compared to starting fragments,” explained first author Blessy Suresh, a graduate student in Disney’s lab. “We were able to screen 460 fragment-based probes in just a couple of hours. This screening method can be easily scaled up to a much more high-throughput format.”

“For every protein encoded in human DNA, there are 75 or 80 types of RNA encoded, so this new tool offers great hope for virtually all diseases now deemed ‘undruggable,’ including triple-negative breast cancer,” Disney said.

This new tool offers hope for undruggable diseases such as triple-negative breast cancer and shows that undruggability will no longer be a match for precision medicine.

“…It may be time to describe biomolecules that are perceived to be challenging small molecule targets as ‘not yet drugged’ rather than ‘undruggable.’ As the science of chemical biology advances, it is becoming clear that more and more biomolecules are indeed targetable,” concluded the investigators.