In the sea of proteins in the body, drug researchers zero in on those that cause disease. Of the 20,000 proteins that make up the human proteome, 5,000 are known to play a role in disease. The challenge is to hit them in a way that has a therapeutic effect. Most of the FDA-approved small-molecule drugs target only 600 of these disease-causing proteins, said Jeff Jonker, CEO of Belharra Therapeutics. The rest are considered unmedicated.
Belharra, which splits its operations between San Mateo, Calif., and San Diego, has developed technology that analyzes proteins and identifies molecules that can bind to them, making them druggable. The approach caught the attention of Genentech, which signed a drug discovery partnership with the launch. Belharra is now out of stealth, disclosing $130 million in funding for his research.
Belharra traces its origins to Scripps Research and the laboratories of Christopher Parker, John Teijaro, and Benjamin Cravath. Their research is focused on chemoproteomics, the study of interactions between proteins and small molecules. Traditional tools like mass spectrometry give scientists insight into how molecules and proteins bind and how that binding affects the cell. It’s a well-validated approach, but it’s also limited, Yonker said. He compares traditional approaches to screening molecules to looking at a single strand of tissue and trying to find things that will stick to it. Even if you can see what attaches to that thread, it’s an incomplete view of that thread in the context of a larger piece of fabric.
Instead of looking at a protein in isolation, Belharra studies how one protein interacts with other proteins and how they all work in the context of the whole cell, Jonker said. This approach allows the company to take its library of small molecules and study how they interact with proteins as they change their shapes and structures. Returning to the textile analogy, Jonker said that the way most proteins function is not as a single yarn, but rather as a bundle of yarns that fold over themselves and over others. The ideal target can be found somewhere in that package, Yonker said. Belharra technology gives drug hunters that bigger picture.
There’s more to Belharra technology. First-generation chemoproteomic technologies require certain amino acids to be present in the protein of interest. This is limiting because only a small fraction of drug targets have these amino acids. Belharra claims that its technology can profile the entire proteome without relying on the presence of any specific amino acids. Jonker said the Belharra technology was able to screen proteins in each of their conformations because they are found in every type of cell. The company’s initial research focus is oncology and immunology.
“Every time we screen, we learn where there are interesting protein binding sites, maybe a little bit more about what those binding sites do,” Yonker said. “Over time, we’re building a library of hits and places where you can connect and make an impact.”
Belharra joins a growing group of companies aiming to uncover new insights into the human proteome as a way to find and hit proteins long thought untreatable. The approach of Interline Therapeutics includes analysis of how proteins interact with each other in communities. ProFound Therapeutics works with thousands of proteins that his technology has revealed beyond 20,000 proteins mapped by the Human Genome Project. Nautilus Bio is among the companies providing its proteome analysis technologies in support of the drug research efforts of others. Nautilus’ industrial partners include Amgen and Genentech.
Genentech was familiar with Belharra’s foundational technology, Jonker said. Knowledge goes both ways. Yonker, whose experience includes executive roles at Ambys Medicines and NGM Biopharmaceuticals, also previously worked at Genentech. Under the collaboration agreement, Belharra is responsible for the discovery and early preclinical development of small molecules targeting targets identified by Genentech. This research will cover cancer, autoimmune and neurodegenerative diseases. Genentech will take over the management in the late preclinical phase and be responsible for the development of the molecules thereafter. Belharra receives $80 million in cash up front; milestone payments could exceed $2 billion. The deal also allows Belharra to co-develop certain oncology or immunology programs.
Versant Ventures formed Belharra about 18 months ago. Tom Woiwode, managing director of the venture capital firm and Belharra board member, said Versant has a close relationship with Scripps and Cravatt in particular has helped identify the “rising stars” of the institute’s research. Versant previously invested in Vividion, a proteome assay a startup based on Cravatt’s research that spun off from Scripps in 2017 and continued to be acquired by Bayer for $1.5 billion in 2021
Belharra initially worked within the Inception Discovery Engine, Versant’s San Diego-based startup incubator. There, Scripps and Belharra scientists worked together to further develop the company’s technology. Versant invested $50 million in the startup’s Series A funding round. Jonker said Belharra waited until the collaboration with Genentech was in place before announcing the general funding behind the company. The Belharra technology is a platform that puts the company in a position to seek other collaborations, Yonker said. He points to Vividion’s path as an example. This company’s technology attracted Bristol Myers Squibb and Roche as collaborators.
San Diego, where Belharra maintains lab operations, has good surfing (the startup’s break room has a surfboard emblazoned with the company’s logo), but the biotech’s moniker was inspired by another region. It is named after a reef off the southwest coast of France that is a popular surfing spot, Woiwode said. Under the right conditions, the site produces massive waves that some in the surfing community describe as “liquid avalanche.” The name Belharra is meant to convey the size of the opportunity the company is pursuing.
“That’s the idea,” Woiwode said. “Go big, the next wave of innovation in chemical proteomics.”
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