Although many proteins are known to cause or play a role in disease, some of them remain unavailable for new therapies because they lack places where small-molecule drugs can attach. One solution is a “molecular glue” that holds together molecules that normally wouldn’t interact. Bristol Myers Squibb is looking for the glue, and it’s turning to a startup for help.
Next partnership Announced Tuesday, A-Alpha Bio will use its technology to analyze protein-protein binding to discover interactions that could lead to promising new glues for its new big pharma partner. Specific financial terms were not disclosed.
Molecular glues have generated interest in a growing field of drug research known as targeted protein degradation. This method uses the cell’s built-in system to remove damaged proteins, using it to eliminate disease-causing proteins. Cells recognize these proteins for processing by molecular tags attached to them. For proteins that have no place to attach this tag, molecular glue can help.
A-Alpha’s machine learning technique finds molecular glue by looking for interactions between ligases, which are the enzymes that regulate this labeling process, and their potential targets. David Younger, co-founder and CEO of the Seattle-based startup, said the research focused on finding weak interactions between ligases and targets. Molecular glues can enhance these weak interactions, but the challenge is finding them in the first place. Younger likens these protein relationships to a lock and key relationship that works when the complementary surfaces of each protein match. Molecular glue acts like an extra bump on a key, making it a perfect fit, Younger said in an email.
“What we can do now, much better than a year ago, is to comb through all the combinations of many ligases and targets and find not only the ‘suitable’ but the ‘nearly suitable’ ones,” explains Young. “These weak interactions then serve as a starting point for the partners to discover the molecular glue that enhances protein-protein interactions.”
The molecular glue research of BMS has focus on the brain, a protein that is a key part of the cellular protein degradation machinery. The goal is to develop molecular glues that alter the binding properties of cereblon to facilitate its interaction with pathogenic proteins. Potential disease targets for the study include cancer and lupus, the company explained in an upcoming 2021 video.
BMS has turned to other startups to advance its protein degradation ambitions. In May, the pharma giant launched a Allied with Amphista Therapeutics Under the agreement, the two companies will jointly discover and develop new small molecules for targeted protein degradation. The Cambridge, UK-based startup claims its technology has advantages over earlier approaches to targeted protein degradation, such as reducing the risk of tumors becoming resistant to treatment. Amphista also says its technology offers the potential to cover a wider range of tissue types in the body.
Amphista received an upfront payment of $30 million from BMS and could earn an additional $1.25 billion in milestone payments. The startup will also be entitled to royalties from the sale of any commercialized products resulting from the partnership.
Advance payment to A-Alpha by BMS is not specified. The deal also qualifies the company for near-term success payments, as well as milestone payments related to research progress. If the research eventually leads to the commercialization of the product, A-Alpha is eligible to receive royalties from the sale.Last year, the company established a similar Research collaboration with Kymera Therapeuticsa clinical-stage developer of drugs that target protein degradation.
here is more about A-Alpha, raised $20 million in Series A funding almost a year ago.
Photos by Flickr users K-State Research and Promotion through Creative Commons license
