New Tool Could Advance Precision Medicine for Incurable Diseases

A new tool that focuses on RNA could accelerate the development of precision medicine treatments for incurable diseases, including a type of metastatic breast cancer, according to a study published in Proceedings of the National Academy of Sciences (PNAS).

Incurable diseases – also referred to as undruggable diseases – typically have targets that lie on a protein molecule that folds inward, or in a way that protects the active site from potential treatments.

To address this issue, a team from Scripps Research developed a tool that avoids these proteins completely, and modifies elements involved in their construction and regulation instead. The tool, called Chem-CLIP-Fragment Mapping, hones in on RNA – molecules that read genes and help build proteins.

Researchers have not viewed RNAs as drug targets until recently, mainly because of issues like short-lived existence, changeable shape, and limited array of building blocks. The Chem-CLIP-Fragment Mapping tool addresses these challenges to enable the rapid discovery and optimization of RNA-targeting compounds.

“It allows us to tackle very hard molecular recognition problems to enable us to make lead medicines across multiple indications,” said Matthew Disney, PhD, of Scripps Research. “This opens great potential to redefine what’s truly ‘undruggable.’”

The tool leverages a recent advance in protein-targeting drug-discovery which uses binding, drug-like chemical fragments to reveal promising templates. Fragments are functionalized, or joined with tags and light-sensitive, allowing researchers to see and identify the fragments.

The Scripps Research team utilizes technologies and databases developed in Disney’s lab over a decade to use the tool with RNA.

The Chem-CLIP-Fragment Mapping system speeds drug discovery efforts because it can reveal multiple opportunities to bind and modify RNA targets. This can help scientists design and optimize potential medicines to bind more tightly, be more specific, and less likely to have off-target side effects right from the start, saving time.

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

In the study, the team used the system to find compounds for microRNA-21, a critical RNA involved in triple-negative breast cancer. This type of breast cancer is very aggressive and lacks precision medicine treatments.

“The system helped us optimize the fragments to design bioactive complexes with higher selectivity and potency as compared to starting fragments,” said 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.”

Most people diagnosed with breast cancer respond to precision medicine therapies, researchers noted, including those that act on the hormones estrogen or progesterone or those that target a protein called HER2. People whose cancer doesn’t fit either one of these categories are referred to as triple-negative, which affects ten to 15 percent of all people diagnosed with breast cancer.

These breast cancers tend to have a worse prognosis because some key proteins are considered undruggable.

Using a light-sensitive module called a diazirine group, the Chem-CLIP-Fragment Mapping tool covalently crosslinks to RNA with exposure to UV light.

“This is a chemical that has a weak magnet-like attraction to other nearby molecules. So when it’s placed near disease-associated proteins, or now RNAs, it can thus bind to them, revealing the shape a medicine would need to take to bind to that disease-associated protein or RNA,” Disney said.

With the new RNA tool, researchers found that they can still search for precision medicine treatments for undruggable conditions.

“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.