There’s a receptor on cells in the gut thought to be associated with a range of gastrointestinal disorders. Some efforts are underway to target this receptor to treat gut inflammation. ThirtyFiveBio is pursuing the target to treat cancer and the biotech startup has chosen the American Association for Cancer Research’s (AACR) annual meeting to reveal its science.
The name of Oxford, U.K.-based ThirtyFiveBio comes from the receptor it’s targeting: GPR35. This receptor belongs to the family of proteins known as G-protein coupled receptors, or GPCRs. The involvement of this protein family in biological processes throughout the body make it valuable for drug research. But less is known about some GPCRs, leaving their role as drug targets less certain. GPR35 is one of these so-called orphans. Orphan GPCRs don’t have endogenous ligands, the substances in the body that can bind to it to produce some sort of an effect. Without known endogenous ligands, it’s hard for drug hunters to completely understand these receptors—that’s why they’re called orphans.
GPR35 was discovered in 1998. Subsequent research linked it to a wide range of disorders, including inflammatory bowel disease, type 2 diabetes, and coronary artery disease. In more recent years, research has yielded genetic insights showing that variants in the GPR35 gene are associated with disease in the gut, said ThirtyFiveBio CEO James Westcott. Those insights have sparked new research at several companies.
Tokyo-based Sosei Heptares has technology that stabilizes GPCRs, aiding in the development of molecules that can target them—including orphan receptors. GPR35 is the focus of Sosei Heptares’s GSK alliance, which started in 2020. The deal gives the pharmaceutical giant rights to Sosei Heptares’s agonists, molecules designed to activate the receptor. In addition to a lead compound in preclinical development for inflammatory bowel disease and other gastrointestinal immune disorders, the deal includes back-up compounds that target GPR35.
Intrinsic Medicine is developing drugs derived from carbohydrates found in human milk. The Seattle company’s preclinical pipeline includes one compound, OM003, an agonist of GPR35 that is being researched as a potential way of treating immune-mediated disorders and inflammatory disorders of the gastrointestinal tract.
ThirtyFiveBio is taking the opposite approach by developing drugs that block GPR35. Westcott said his company’s research into human data shows that the receptor is switched on in diseases states, suggesting that turning it off would be a better way to affect disease.
At AACR on Sunday, ThirtyFiveBio is presenting its GPR35 research. In an abstract submitted for the conference, the company notes that a fatty diet combined with metabolism in the gut can lead to high levels of secondary bile acids that raise the cancer risk. These bile acids can activate GPR35. ThirtyFiveBio’s drug discovery work has yielded small molecules that block GPR35 signaling that promotes cancer. These molecules also block the signaling that comes from secondary bile acids.
Westcott said ThirtyFiveBio has four compounds that have reached lead optimization. The company won’t be disclosing their chemical structures at AACR. The presentation will focus on the startup’s research into GPR35, he said. The company will also show it has potent inhibitors of the receptor whose mechanism of action is understood.
“We’ve validated the hypothesis in translational models of disease,” Westcott said. “That’s what we’ve done to step out and tell the world about.”
ThirtyFiveBio’s science is rooted in M:M Bio, a company that has a record of incubating and starting biotechnology firms. Pathios Therapeutics was the first one, founded in 2017. That startup’s research focuses on another orphan, GPR65, for potential applications in cancer immunotherapy. Bioinformatic analysis of that receptor also turned up signals indicating that blocking GPR35 could be promising as well, Westcott said. Pathios’s 2019 Series A financing included an investment from venture capital firm Canaan Partners, whose portfolio includes cancer drug developers Rondo Therapeutics and Day One Biopharmaceuticals.
In 2021, M:M Bio founded ThirtyFiveBio in partnership with Canaan. To date, the startup has raised $20 million in seed financing. With the preclinical data the it has generated, Westcott said the company will look to extend that financing to validate the path to human testing. He added that ThirtyFiveBio would look to raise a Series A financing in “a couple of years” to reach the clinic.
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