Each year, Nature Biotechnology highlights companies that have received sizeable early-stage funding in the previous year. Gate Bioscience wants to tailor gates that stop problematic proteins at the source.
His company is developing ‘molecular gates’ as a new class of medicines with a new mechanism of action, says Jordi Mata-Fink, CEO and co-founder of Gate Bioscience, headquartered in Brisbane, California, just across the South San Francisco city line. The fundamental idea of molecular gates, says Pat Sharp, scientific founder and vice president for discovery science at Gate Bioscience, builds on research that reaches back around three decades. The idea is to intervene “at the source” and eliminate disease-causing proteins.
S. Humphrey
Jordi Mata-Fink, CEO of Gate Bioscience
Around one-quarter of the more than 4,000 extracellular proteins in humans can cause diseases, ranging from cancers and neurological disorders to autoimmune conditions. But it’s not a one-to-one match between disease and protein, says Mata-Fink. Rheumatoid arthritis, for instance, can be caused by several misacting proteins. A protein might be too abundant or present at the wrong place or time, as in some autoimmune diseases. Or a protein can be misfolded, as in prion disease. In such cases, “if you could eliminate that protein, you could eliminate the disease,” he says.
The targeted exclusion of proteins involves steps at a conduit called Sec61, through which proteins pass on their way from inside to outside the cell. Sec61 is a membrane protein in the endoplasmic reticulum (ER).
Gate Bioscience is designing molecular ‘gates’ that bind to locations in Sec61 to block a specific protein from passing through. The gates “essentially redirect it to be degraded by the cell’s natural cleanup mechanisms,” says Mata-Fink.
The three years since Gate Bioscience’s founding have “gone by in the blink of an eye,” he says. And “we’ve also come a really long way.” The company now has 30 staff members and emerged from stealth mode in November 2023 with coffers of $60 million from a Series A funding round led by Versant Ventures and a16z Bio+Health alongside ARCH Venture Partners and Google Ventures. Before his role at Gate Bioscience, Mata-Fink built startups as part of Flagship Pioneering’s Labs team.
“We love platform biotech companies,” notes Vineeta Agarwala from a16z Bio+Health in a blog post. The ‘platform’ is the common mechanism of action for the therapeutics in Gate Bioscience’s sights. This commonality, says Raman Talwar, Gate Bioscience co-founder and CTO, can make their small-molecule development process more efficient.
Existing approaches to eliminate proteins therapeutically include the use of CRISPR to disrupt the gene encoding a protein of interest and RNA-based therapies such as siRNA or antisense oligonucleotides that silence the RNA to prevent the production of a specific protein. Antibody drugs can bind to a protein target and silence it. But these drugs are administered by injection or infusion, which can be inconvenient for patients, says Mata-Fink. as sizeable biologics, they also don’t readily enter tissues such as the brain. Small molecules will be more practical for patients and potentially more effective because they can reach any location in the body.
Gate Bioscience eyes many disease areas but has only publicly disclosed three disease programs, all in similar preclinical development stages, says Mata-Fink. One targets prion protein in prion diseases. The company is not disclosing the other two.
The fundamental insight that molecules can bind to Sec61 originated in the early 1990s, says Sharp, when two companies working separately, Shionogi and Novartis, came across naturally occurring Sec61 inhibitors. Novartis published its findings1. Interest in this area grew as researchers discovered that the compounds intervened in Sec61’s role in protein secretion.
Jack Taunton at the University of California, San Francisco (UCSF), along with colleagues at the National Institutes of Health and a company called Bioseek, published their research on a small molecule that inhibits the translocation of a protein through the Sec61 complex2.
These papers, says Sharp, “sort of cracked the mechanism of how these molecules work and that they bind to Sec61.” Interest in Sec61 inhibitors also grew in the UCSF lab of Jack Taunton, which Sharp joined in 2015. As Sharp tinkered with the inhibitors’ chemical structure to make them more drug-like, he assessed their activity. Around this time, the promise of targeted protein degradation with PROTACs, or proteolysis-targeting chimeras, was taking hold. It was “the tailwind that really helped boost this field,” says Sharp, and it led to Gate Bioscience’s founding.
What’s crucial about Sharp’s work, says Mata-Fink, is how structural tweaks tune the inhibitors’ potency and selectivity. Other work on targeting protein biogenesis had faced some toxicity challenges, as Sharp and colleagues noted in their paper.
In 2023, Sharp coauthored a paper with Taunton and colleagues in Finland and at Kezar Life Sciences on a compound that selectively inhibits inflammatory cytokines3. By binding to part of Sec61 with a tuned small molecule, it blocked cytokines from moving through the channel.
At the same time, Eunyong Park of the University of California, Berkeley, with colleagues at Berkeley and other institutions and the Basel, Switzerland, campus of Novartis Institutes for BioMedical Research, published high-resolution structural data on Sec61 inhibited by a panel of small molecules and mechanistic findings on the inhibitors4. Although the inhibitors were structurally distinct, they all worked similarly: they blocked the channel by occupying the same site in Sec61, says Park.
Given that around one-third of a cell’s proteins are produced in the ER, says Park, it’s a good spot to intervene. Most current drugs work by inactivating a target protein. But by inhibiting at the ER’s Sec61, one can block “the conduit these proteins use to reach their final destination.” Gate Bioscience focuses on Sec61. Kezar Life Sciences, an Amgen spinout that Park has connections to, has focused on inhibiting protein secretion from cells.
In the ER’s long, labyrinthine membrane, Sec61 has around 5,000 different ‘client proteins,’ only some of which are pathological. When Sec61 ‘bounces’ a protein, degradation by the cell’s ubiquitin–proteasome system follows. Bounced proteins could develop activity that harms the physiology of a cell, Park says, but that will vary from protein to protein, and experiments would be needed to test it.
Assorted structural data, including cryo-electron microscopy findings, have emerged about Sec61 and Sec61 inhibitors, “but there are still many exciting things to be discovered about these molecules,” says Park. The list of Sec61 inhibitors, both natural occurring and synthetic, has grown substantially in recent years. “I am certain that there will be a lot more to come,” he says. Of its disease programs, Gate Bioscience has only disclosed one, which is prion disease. He is not a prion expert, says Song, but these proteins are known to aggregate. To effectively suppress prion protein may, in his view, take more than gating at Sec61.
A main challenge in the field, says Park, is blocking Sec61 selectively and preventing the production of only one target protein. Completely blocking Sec61 would kill cells, and many naturally occurring Sec61 inhibitors are too toxic to be drugs, he says. “Although this sounds like an extremely difficult task, the bright side is that there are already a couple of known examples of such selective Sec61 inhibitors,” says Park. Several groups focus on more selective compounds for different target proteins. “My lab is interested in understanding the principles by which such selectivity is generated,” he says.
Mata-Fink is glad the company can draw on the experience of chairman Tom Daniel. While at Celgene, Daniel led development of a molecule class called molecular glues. These stick to a protein and target it for elimination in the cell’s disposal system. Gate Bioscience’s CSO was also at Celgene. Says Mata-Fink, “Putting those people around the table with us will help, I think, make the company more successful.”
Source : Nature.com