In the sea of proteins in the body, drug researchers are navigating to the ones 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 hitting them in a way that has a therapeutic effect. Most of the FDA-approved small molecule drugs address just 600 of these disease causing proteins, said Jeff Jonker, CEO of Belharra Therapeutics. The rest are considered undruggable.
Belharra, which splits its operations between San Mateo, California and San Diego, has developed technology that analyzes proteins and identifies molecules that can bind to them, making them druggable. The approach caught the eye of Genentech, which has inked a drug discovery partnership with the startup. Now Belharra is out of stealth, revealing $130 million to fund its research.
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Belharra traces its origins to Scripps Research and the labs of Christopher Parker, John Teijaro, and Benjamin Cravatt. Their research focused on chemoproteomics, the study of the interactions between proteins and small molecules. Traditional tools such as mass spectrometry give scientists a view into the way molecules and proteins bind and how that binding affects a cell. It’s a well validated approach, but it’s also limited, Jonker said. He compares traditional approaches of screening molecules to looking at a single thread of fabric 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.
Rather than viewing a protein in isolation, Belharra studies how a protein interacts with other proteins and how all of them operate in the context of the whole cell, Jonker said. This approach enables 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 textiles analogy, Jonker said that the way most proteins function is not as a single yarn, but rather as a bundle of yarns that fold upon themselves and others. The ideal target can be found somewhere on that bundle, Jonker said. The Belharra technology gives drug hunters that bigger-picture view.
There’s more to the Belharra technology. First-generation chemoproteomics technologies require certain amino acids to be present on the protein of interest. That’s limiting because only a fraction of drug targets have those amino acids. Belharra claims its technology can profile the entire proteome without relying on the presence of any specific amino acids. Jonker said the Belharra technology has been able to screen proteins in any of their conformations as they’re found in any cell type. The company’s initial research focus is oncology and immunology.
“Every time we do a screen, we learn where there are interesting binding sites on proteins, maybe a little more about what those binding sites do,” Jonker said. “As time goes by, we’re building up a library of hits and spots where you can bind and have an effect.”
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Belharra is joining a growing group of companies aiming to uncover new insights into the human proteome as a way of finding and hitting proteins long thought to be undruggable. The approach of Interline Therapeutics involves analyzing how proteins interact with each other within communities. ProFound Therapeutics is working with the thousands of proteins that its technology has uncovered beyond the 20,000 proteins mapped by the Human Genome Project. Nautilus Bio is among the companies providing their proteome analysis technologies in support of the drug research efforts of others. The industry partners of Nautilus include Amgen and Genentech.
Genentech was familiar with Belharra’s foundational technology, Jonker said. The familiarity goes both ways. Jonker, whose experience includes executive roles at Ambys Medicines and NGM Biopharmaceuticals, also previously worked at Genentech. Under the collaboration agreement, Belharra is responsible for discovery and early preclinical development of small molecules addressing targets designated by Genentech. This research will span cancer, autoimmune, and neurodegenerative diseases. Genentech will take over at the late preclinical stage and be responsible for developing the molecules thereafter. Belharra receives $80 million in cash up front; milestone payments could top $2 billion. The deal also gives Belharra the option to co-develop certain oncology or immunology programs.
Versant Ventures formed Belharra about 18 months ago. Tom Woiwode, managing director at the venture capital firm and a Belharra board member, said Versant has a close relationship with Scripps, and Cravatt in particular has helped identify the “rising stars” out of the institute’s research. Versant had previously invested in Vividion, a proteome analysis startup based on Cravatt’s research that spun out of Scripps in 2017 and went on to be acquired by Bayer for $1.5 billion in 2021.
Belharra initially operated within Inception Discovery Engine, Versant’s San Diego-based startup incubator. There, scientists from Scripps and Belharra worked together to further develop the company’s technology. Versant invested $50 million for the startup’s Series A round of financing. Jonker said Belharra waited until the Genentech collaboration was in place before announcing the total financing behind the company. The Belharra technology is a platform that puts the company in position to seek out other collaborations, Jonker said. He points to Vividion’s path as an example. That 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’s named for a reef off of 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 a “liquid avalanche.” The Belharra name 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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