One of the hottest areas of therapeutic research harnesses the part of a cell that breaks down old or damaged proteins, using it as a way of getting rid of the proteins that cause disease. But sometimes the opposite is needed. For some diseases, therapeutic benefit can come from having certain proteins stick around longer.
Stablix Therapeutics is developing technology that keeps a target protein from going to the cellular disposal system. The startup is pursuing applications of the technology in rare diseases, cancer, and immunology, and it launched last week with $63 million in funding. Versant Ventures, Stablix’s founding investor, led the Series A financing.
Using a cell’s built-in components to get rid of disease-causing proteins is called targeted protein degradation. This approach uses small molecules to mark a problem protein so that it gets recognized for disposal. It accomplishes this by attaching ubiquitin, a protein that acts like a tag that identifies it for the proteasome, the cell’s protein-disposal machinery.
Targeted protein degradation has led to hundreds of millions of dollars in venture capital investment poured into startups, partnerships with large pharmaceutical companies, progress into the clinic, and IPOs for biotechs including Kymera Therapeutics, C4 Therapeutics, Arvinas, and Nurix Therapeutics. Versant has also invested in targeted protein degradation. Last year, Versant launched Lycia Therapeutics, backing its approach to protein degradation with $50 million in funding. The San Diego-based startup is developing drugs that address hard-to-target proteins.
The inverse of protein degrading drugs is what Stablix calls targeted protein stabilization. The startup’s technology platform also uses small molecules, but instead of trying to mark a target protein so it’s recognized by the proteasome, these molecules recruit different enzymes that remove ubiquitin from the desired protein. Consequently, the levels of that target protein are stabilized in the cell.
Stablix offers some examples in which protein stabilization could help patients. In cystic fibrosis, mutations to the CFTR gene produce a protein that is functional, but is excessively tagged by ubiquitin, leading to its rapid degradation. In cancer, levels of the enzymes that add ubiquitin to proteins increase, which in turn drives the degradation of tumor suppressor proteins.
Some drugs already leverage this concept of stopping a protein from being broken down in a cell. As their name suggests, proteasome inhibitors block the proteasome from breaking down proteins. This class of drugs has approvals in multiple myeloma. But proteasome inhibitors aren’t specific in the way that they block a protein from being degraded, which limits their use outside of cancer, Stablix said. The company contends that its technology offers a more targeted approach.
The Stablix technology comes from the research of Henry Colecraft, a co-founder of the company and a Columbia University professor of physiology and cellular biophysics. He and fellow co-founder Scott Kanner developed a way to selectively recruit the enzymes that remove ubiquitin from a protein of interest. Their research was able to rescue CFTR, the key protein in cystic fibrosis. They were also able to apply their technology to the KCNQ1 gene, which leads to the heart disorder long QT syndrome when that gene is mutated. The CFTR and KCNQ1 research was described in a paper, whose co-authors include Colecraft and Kanner, published last November in Nature Methods.
Stablix is led by acting CEO Carlo Rizzuto, a partner at Versant. Other investors in the Series A financing were NEA, Cormorant, Euclidean Capital, and Alexandria Real Estate Equities. Stablix has established a lab in New York City. With the fresh capital in hand, the company plans to build out its technology platform and advance a portfolio of protein stabilizing-drugs toward human testing.
Photo by Flickr user Rob Nguyen via a Creative Commons license
