Although many proteins are known to cause or play a role in disease, some remain inaccessible to new therapies because they lack sites where a small molecule drug can attach. One solution is a “molecular glue,” which causes molecules that normally don’t interact to stick together. Bristol Myers Squibb is chasing such adhesives and is turning to a startup for help in discovering them.
Under a partnership announced Tuesday, A-Alpha Bio will use its technology to analyze protein-protein binding to discover the interactions that could lead to promising new adhesives for its new, big pharma partner. Specific financial terms were not disclosed.
Molecular adhesives are of interest to a growing area of drug research called protein targeting. This approach exploits the cell’s built-in damaged protein clearance system, using it to eliminate disease-causing proteins. The cell recognizes these proteins for disposal by a molecular marker that is attached to them. For proteins that have nowhere to attach this tag, a molecular glue can help.
A-Alpha’s machine learning technology finds molecular glues by looking for interactions between ligases, which are enzymes that regulate this labeling process, and their potential targets. According to David Younger, co-founder and CEO of the Seattle-based startup, this research focuses on looking for weak interactions between ligases and targets. These weak interactions can be improved with a molecular glue, but the challenge is finding these interactions in the first place. Yanger likened the relationship of these proteins to that of locks and keys that work when the complementary surfaces of each match. The molecular glue is like the extra protrusion on the key that makes it a perfect fit, Younger said in an email.
“What we can do now, much better than we could a year ago, is search through all the combinations of many ligases and targets to find not only those that ‘fit’ but also those that are ‘almost “, Junior explained. “These weak interactions then serve as a starting point for the partner to find a molecular glue that enhances the protein-protein interaction.”
BMS research on molecular glue has focused on the cerebro, which is a protein that is a key part of the protein breakdown machinery in the cell. The goal is to develop molecular glues that alter the binding properties of cereblon to promote its interaction with disease-causing proteins. Potential targets for this research include cancer and lupus, the company explained in a follow-up video from 2021.
BMS has turned to other startups to advance its protein-degrading ambitions. In May, the pharmaceutical giant launched alliance with Amphista Therapeutics under which the two companies will work together to discover and develop new small molecules with applications in targeted protein degradation. The Cambridge, UK-based startup claims that compared to earlier approaches to target protein degradation, its technology has advantages such as reducing the risk of tumors becoming resistant to therapy. Amphista also says its technology offers the potential to reach a wider range of tissue types in the body.
Amphista received a $30 million upfront payment from BMS and could earn up to $1.25 billion more in milestone payments. The startup will also be entitled to royalties from sales of any commercialized products that result from the partnership.
BMS’ advance payment to A-Alpha is not specified. The deal also makes the company eligible for short-term success payments, plus principal payments related to research progress. If this research ultimately results in a commercialized product, A-Alpha is eligible for sales royalties. Last year, the company did the same research partnership with Kymera Therapeuticsa clinical-stage developer of targeted protein degradation drugs.
Here’s more about A-Alpha, which raised $20 million in Series A funding almost a year ago.