Proteasome inhibitors (QLi5 Therapeutics)

When proteins cause disease, the body has ways to tackle them. An emerging class of therapies that leverage a cell’s built-in systems to eliminate rogue proteins has already reached the clinic via several companies. But there’s more than one way to get cells to degrade disease-causing proteins, and Booster Therapeutics is developing drugs that could expand this approach to more proteins and more diseases. Neurodegeneration is Booster’s initial focus, and the startup launched out of stealth Thursday backed by $15 million in funding. The protein-degrading drugs currently in clinical development direct disease-causing proteins to a component of a cell called the proteasome. The drugs themselves are small molecules that recruit a molecular tag that marks a protein for disposal by the proteasome. Companies developing targeted protein degraders include Kymera Therapeutics, Arvinas, and Nurix Therapeutics. All three have research alliances with big pharmaceutical companies. Most of the degraders currently in development are for cancer, but this field is also pursuing immunological disorders. There are limitations to the current approach of degrading proteins, said Booster co-founder and Chief Scientific Officer Diogo Feleciano. These protein-degrading drugs each address only a single disease-causing protein, but some diseases are driven by multiple proteins. Targeted protein degradation also requires a molecular tag. Without it, the proteasome leaves proteins alone. presented by Sponsored Post The Promise of Value-Based Care and MedTech Innovation Monica Vajani, Executive Director for mHUB’s MedTech Accelerator, discusses how mHUB is helping innovators transition healthcare towards value-based care. By Monica Vajani - mHUB Cells have other types of proteasome besides the one that’s the focus of targeted protein degradation, and Feleciano says it’s here where Booster stands apart. Berlin-based Booster focuses on the 20S proteasome, which is capable of addressing multiple proteins without needing a tag to mark them for degradation. Cells have ways to control whether proteins are degraded or not, Feleciano said. The 20S proteasome naturally addresses proteins that are misfolded. In some diseases, these problem proteins aggregate and overwhelm the proteasome, which then becomes inactive. The startup is developing small molecules that specifically target 20S proteasomes to give them a pharmacological boost. “What we are aiming to do with our molecules: Restart, reactivate that function to homeostatic levels,” Feleciano said. “By doing that, we can improve the degradation of proteins and alleviate the accumulations that are known to be toxic.” Drug research has already yielded drugs that target the proteasome. For example, proteasome inhibitors treat multiple myeloma by stopping proteasomes from getting rid of proteins that are no longer useful. The resulting protein accumulation leads to death of cancer cells. But scientists have been pursuing ways to activate proteasomes to treat disease, a field that Feleciano acknowledges did not start with Booster. Feleciano’s Ph.D. research covered neurodegeneration, including the role of the proteasome in such diseases. He said that work sparked interest in therapeutics that could address the proteasome and form the basis of a company. He found promising science in the lab of Darci Trader, a professor in the department of pharmaceutical sciences at the University of California, Irvine, whose research focuses on chemically stimulating the 20S proteasome in neurons. Parkinson’s disease is one area of focus of Trader’s research. Booster incorporated in 2020 with Trader as its scientific co-founder. The startup has been incubating within Apollo Health Ventures, the venture capital firm where Feleciano is an entrepreneur in residence. 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With the capital, Feleciano said Booster will continue to build the company and advance the development of its programs. “We are not only pioneering activation of the proteasome, we are pioneering knowledge of what that means,” he said. “We are building more knowledge of what is out there. This is an area that is untapped.” Image: akindo, Getty Images