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For many diseases, the challenge is more than identifying the disease-causing protein, it’s getting a drug to stick to it. One solution is a molecular glue, a small molecule that gets proteins that don’t normally interact to stick together. Biotech startup Ambagon Therapeutics is applying its molecular glues to some of the most difficult-to-target proteins, and the preclinical biotech has raised $85 million to advance research that is initially focused on cancer.
The Series A financing announced Thursday was led by Nextech Invest.
Small molecule drugs work by binding to a target. That’s not a problem for proteins with an obvious binding site, but not all proteins have such targets. Molecular glues might be best known for the role that they play in an emerging therapeutic approach called targeted protein degradation. This type of therapy involves using a small molecule to get a disease-causing protein to go to the cell’s built-in disposal system.
For proteins that don’t have a pocket to which a small molecule drug can attach, a molecular glue can help. These glues bind the problem protein to a molecular tag that marks it for disposal. Boston-based Monte Rosa Therapeutics is developing protein degradation therapies based on its molecular glue technology. Kymera Therapeutics of Cambridge, Massachusetts, has a pipeline of protein degradation drugs and more recently began a molecular glue discovery partnership with protein-protein interaction startup A-Alpha Bio.
Ambagon’s approach can be used to degrade target proteins, but the biotech is taking a broader view of the potential for its molecular glues. Some proteins are notable for intrinsic disorder, a lack of structure that makes it hard to design a drug that can bind to them. Ambagon’s research focuses on the 14-3-3 family of proteins, which play a key role in many disease-related pathways. According to the company, there are more than 3,000 proteins that interact with 14-3-3 proteins. When these proteins bind to 14-3-3, their intrinsic disorder turns into order, making them druggable. Ambagon, which has operations in San Carlos, California, and Eindhoven, the Netherlands, aims to stabilize naturally occurring 14-3-3 protein interactions. By doing so, the company says target proteins can then be enhanced, inhibited, or degraded. These proteins can also be moved to a desired location or kept away from disease-driving activity.
Cancer-associated proteins that interact with 14-3-3 include Raf kinases, FOXO transcription factors, and tumor suppressor protein p53. In neurological disease, proteins such as tau, alpha synuclein, and the LRRK2 kinase interact with 14-3-3. The Ambagon pipeline so far is comprised of five programs in early discovery addressing undrugged targets associated with various cancer-driving processes. On its website, the company said aims to identify at least one drug development candidate by the second half of 2023.
Ambagon was founded by scientific experts in 14-3-3 biology and the drugging of protein-protein interactions: Michelle Arkin, professor and chair of pharmaceutical chemistry at the University of California San Franisco; Luc Brunsveld, professor of chemical biology at the Eindhoven University of Technology (TU/e); and Christian Ottmann, associate professor of molecular cell and structural biology at TU/e and Ambagon’s chief technology officer. The startup is led by CEO Scott Clarke, the former chief executive of Tizona Therapeutics and Trishula Therapeutics. Ambagon’s chief scientific officer, Nancy Pryer, was the CSO of cancer drug biotech Day One Biopharmaceuticals and the chief development officer of protein degradation biotech Nurix Therapeutics.
“Our deep understanding of 14-3-3 biology has broad applications for drug discovery as it opens up disordered protein regions as therapeutic targets,” Clarke said in the company’s funding announcement. “Combined with our proprietary structural insights, curated chemical library, and bespoke drug discovery tools, our experienced drug development team is well placed to bring forward new medicines addressing previously undruggable targets.”
Ambagon was previously seeded by RA Capital Management, Droia Ventures, Inkef Capital, AbbVie Ventures, MRL Ventures Fund, and Mission BioCapital. Those seed investors also joined the Series A round, along with new investor Surveyor Capital.
Photo by Flickr user K-State Research and Extension via a Creative Commons license