Ribometrix is the latest biotech start-up to raise cash for a bold, but increasingly popular, idea in drug discovery: target RNA with small-molecule drugs.
Kevin Weeks, a chemist at University of North Carolina at Chapel Hill, and his former undergraduate student Katie Warner, founded the Durham-based company and launched with $7.5 million in seed funding just over a year ago. Now Ribometrix has raised a fresh $30 million series A round and is providing hints at how its RNA-targeting technology could be a new way to block the creation of disease-causing proteins in cancer and neurodegenerative diseases.
Ribometrix is joining a suite of other well-funded start-ups pursuing similar RNA-targeting strategies including Arrakis Therapeutics, Expansion Therapeutics, and Skyhawk Therapeutics. Big pharma companies, including Merck & Co. and Novartis, are also quietly working on programs to target RNA with small molecules.
Almost all small-molecule drugs bind to proteins with well-defined structures. RNA, the spindly strand of nucleotides that encodes instructions for making proteins, has long been considered too unstructured to make a good drug target. But RNA scientists are increasingly convinced that some RNAs actually fold into complex structures with nooks and crannies that small molecules can bind to.
Being able to bind RNA could help scientists who are confronted with disease-related proteins that are considered “undruggable” because they lack footholds for small molecules. Targeting the messenger RNAs (mRNAs) that encode these undruggable proteins could provide a powerful workaround, says Mike Solomon, Ribometrix’s CEO.
Ribometrix is disclosing two programs to pursue this strategy. One is to target the mRNA that produces c-Myc, a protein whose haywire activity promotes many cancers. The other is to target the mRNA that produces the mutant huntington protein in Huntington’s disease. Separately, Ribometrix has programs targeting microRNAs, which are involved in regulating the activity of many different genes.
The start-up’s key technology, first developed by its cofounders 10 years ago, is a chemical-probing technique for determining RNA structure called selective 2-hydroxyl acylation analyzed by primer extension, or SHAPE. The original version of SHAPE only determined the two-dimensional structures of RNA (Proc. Natl. Acad. Sci. 2009, DOI: 10.1073/pnas.0806929106). Since then, Weeks and Warner have developed advanced iterations of SHAPE to determine the three-dimensional structures of RNA and have applied the method to study a variety of human and viral RNAs.
“When I saw the RNAs’ structure, it looked like a protein. And from a drug discovery perspective, that’s great,” says Solomon, who trained as an organic chemist and is now a partner at the venture capital firm SV Health Investors, a founding investor in Ribometrix. In the past year, the start-up has also developed a version of SHAPE that can be used to screen for compounds that bind RNA.
Weeks emphasizes that the goal is to make drugs that don’t look noticeably different from one that would bind a protein. “This is a key thesis of the company, he says. “If you find the right RNA target, then you can target them with standard, normal-looking small molecules.”
Ribometrix isn’t disclosing any timelines for getting drug candidates into the clinic, and it will likely be a few years before the start-up, or its competitors, is able to offer any evidence that the RNA-targeting hypothesis will work in humans.