In biology, structure determines function. For decades, drug discovery has capitalized on this relationship by seeking out and designing compounds that change protein behavior by fitting into easily bound structural features.
Yet the lock-and-key relationship exploited by most current drugs represents only a fraction of existing opportunities to interfere in disease-causing pathways. Just as the majority of the universe consists of dark matter invisible to telescopes and other astronomical instruments, there is a vast and rich untapped realm beyond the reach of traditional methods. This domain of the “undruggable,” as it is sometimes called, may exceed the biological reach of current drugs six-to-one. One of its most innovative trailblazers, Ambagon Therapeutics, launched at MBC BioLabs in 2020.
Ambagon focuses on disordered proteins, which occupy one of the most difficult to reach and potentially fertile regions of undruggability. These proteins offer limited structure for a drug to bind or contain significant regions lacking organization. Proteins with disordered domains play important roles in disease pathways, driving processes linked to uncontrolled cell division in cancer, metabolic imbalances in diabetes, and neurodegeneration in diseases like Parkinson’s and Alzheimer’s.
In more than two decades of research, Christian Ottmann of the Eindhoven University of Technology in The Netherlands has shown how hundreds of the most disease-relevant disordered proteins bind to another protein, called 14-3-3, which temporarily stabilizes them in preparation for some biological interaction.
Ottmann joined colleagues Michelle Arkin of the University of California San Francisco and Luc Brunsveld of TU/Eindhoven to found Ambagon Therapeutics. The company’s goal is to discover “molecular glues,” small-molecule compounds that can strengthen the bond between 14-3-3 and an individual client protein to produce a therapeutic effect.
“14-3-3 grabs a floppy unstructured region of a client protein and forms it into a structured domain; now there is something a small molecule drug can bind to,” says Nancy Pryer, Ambagon’s chief scientific officer. “We want to stabilize that structured interaction.”
The company is initially focused on cancer, where 14-3-3 stabilization of client proteins has the potential to interfere with a broad spectrum of oncogenic processes. The approach is exciting because the consistent features of interactions between 14-3-3 and clients provides a modular way to drug many different disordered proteins, while the unique details of each particular complex favors selectivity.
“The 14-3-3 protein forces the client protein into a particular conformation in a binding cleft, leaving a specific empty space for a small molecule to fill,” Ottmann says. “Our platform consists of several tools that enable us to create compounds to occupy that space and show that they have important biological effects.”
Ambagon’s early efforts have been supported by two MBC Biolab Golden Tickets and $18 million in seed funding from venture and strategic investors, including RA Capital, Droia Ventures, Inkef Capital, AbbVie Ventures, Merck, and Mission Bay Capital.
“Creating a launchpad for ambitious companies like Ambagon is exactly why we created MBC BioLabs,” says Douglas Crawford, MBC BioLabs General Manager. “We are excited to see how Ambagon redefines which targets are druggable.”