Molecular Multi-Tools Turn Existing Drug into RNA-Targeting Compound

Journal of the American Chemical Society, DOI:

Metastatic breast cancer and Alport syndrome respond to the new compounds, offering a strategy for broadly tackling untreatable diseases.

JUPITER, FL—Like a carpenter switching drill bits depending on the job at hand, scientists at Scripps Research in Florida have changed an investigational medicine’s activity by swapping in different molecular tools, in the process, showing a potential new way to address multiple incurable diseases.

Invented by chemist Matthew Disney, PhD, the new molecular tools break up disease-causing microRNAs or prevent their assembly, depending on which tool is selected. Experiments in mice showed the altered compounds successfully stopped progression of metastatic triple-negative breast cancer tumors in mice, and repaired kidney damage in a mouse model of Alport syndrome, a genetic disease that leads to fibrotic kidney damage.  

Disney and colleagues believe the technique of modifying known, safe drugs with such tools could have broader applications for addressing a variety of currently untreatable diseases, and on an accelerated timetable.

While most medicines work by acting on disease-causing proteins, not all conditions have structurally druggable targets. Redirecting existing therapeutics with RNA-binding “drill bits” offers a strategy for accelerating progress on multiple conditions, Disney says.

“These studies may establish a foundation for reprogramming other known drugs for disease-associated RNAs,” Disney and his colleagues write in their study, published online August 16 in the Journal of the American Chemical Society.

Starting from existing drugs

RNA are molecules involved in making and regulating proteins in cells. They have until recently been an unrealized drug target due to their unstable, changeable structure. Thanks in large part to the inventions from Disney’s lab, major progress has recently been made in overcoming those difficulties.

Simultaneously, a major advance in drug repurposing has emerged at Calibr, the drug discovery division of Scripps Research in La Jolla, California. There, scientists have built a library of most of the world’s known drugs, both approved and experimental. All have undergone some degree of safety testing in humans, making them a valuable resource for moving needed therapies to patients more quickly than would be possible with a totally new drug molecule.

Called ReFRAME, the collection contains more than 10,000 compounds in a format that allows for assessment on a mass scale, with the help of robots.

Painstakingly assembled by Calibr chemists, the ReFRAME collection has helped identify medications for conditions including malaria and cryptosporidium, a leading cause of child deaths globally. It has also been shared with more than 40 research groups globally to assist the fight against the COVID-19 pandemic.

Disney’s team found a way to screen the ReFRAME collection for compounds that bind even weakly with RNA. To do so, they created plates studded with structurally stable, druggable fragments of RNA molecules. That screen revealed that 68 out of 9,300 ReFRAME compounds had an ability to bind to at least one of the stable RNA structures.

Next, they incubated those 68 compounds with another set of compounds that enabled them to fish out ones that would bind with rare, stable RNA structures known to play a role in disease. Four medicines—Dovitinib, Delparantag, Piroxantrone and Metiazinic Acid—currently used to treat multiple diseases, bound RNA targets strongly.

Targeting cancer and more

Dovitinib bound the precursor for microRNA-21 (Pre-miR-21) which is known to play a role in aggressive cancers and in diseases like Alport syndrome that involve creating fibrosis, or buildup of scar tissue, in organs including kidneys. But it also bound another target. Disney’s group fine-tuned the binding of the drug to the desired target with two different approaches, by adding a tool that degrades RNA, or by adding a tool that degrades unwanted proteins.

Both strategies successfully redirected the drug to the desired target and ultimately prevented the disease-causing microRNA from being made. This cleared breast cancer tumors from mouse-models of triple-negative breast cancer and repaired fibrotic tissue in the damaged kidneys of mouse models of Alport syndrome.

“We have shown for the first time that a protein-targeted medicine known to be safe in humans can be rationally reprogrammed to target a microRNA that causes cancer, kidney disease, and cardiovascular disease, among other conditions,” Disney says. “We are really leveraging 10 years of work in the lab for this application. We believe the technique may have broad applications.”

In addition to Disney, the authors of the study, “Reprogramming of Protein-Targeted Small-Molecule Medicines to RNA by Ribonuclease Recruitment,” include first authors Peiyuan Zhang, Xiaohui Liu, Daniel Abegg, Toru Tanaka, Yuquan Tong, Raphael I. Benhamou, Jared Baisden, Gogce Crynen, Samantha M. Meyer, Michael Cameron, Alexander Adibekian and Jessica Childs-Disney, all of Scripps Research in Jupiter, FL; and Arnab Chatterjee of the California Institute for Biomedical Research (CALIBR) at Scripps Research in La Jolla, CA.The work was supported by the National Institutes of Health, the Myotonic US Fellowship Research Grant, and the National Ataxia Foundation Fellowship Research Grant.