Posted November 1, 2023

“Everything is theoretically impossible, until it is done.” —Robert A. Heinlein, American science-fiction writer and aeronautical engineer

Modern medicine is full of awe-inspiring progress, but also many humbling limitations. In the face of these limitations, innovators have consistently propelled entirely new classes of drugs from theoretical concepts that sound like total science fiction (vaccines, antibodies, genetic medicines to reprogram our cells, and more)—into the realm of safe and effective therapies for patients.

Small molecules: the OGs of the therapeutic arsenal

Amidst all this rapid progress, small molecules—the original heroes of the therapeutic arsenal, the original enablers of the “pill” form of drugs we all have in our medicine cabinets—continue to represent ~60% of all new FDA approvals. Small molecules are fantastical in their own right: they are typically orally bioavailable, conveniently administered, cheaper to manufacture, and distribute well throughout many tissues in our bodies (including the brain). They are also most widely accessible to patients: drugs like aspirin, penicillin, statins, and tamoxifen have had tremendous impact on billions of patients globally.

Now, ushered forward by a wave of new and enabling technologies, the field of small molecule discovery is undergoing nothing short of a renaissance. Important classes of targets, however—including thousands of extracellular and secreted protein targets—remain challenging for small molecules to effectively address. This is where Gate Bio comes in.

Gate Bio: engineering cell biology to build a novel class of medicines

Gate Bio is building a new class of small molecules called Molecular Gates. While most small molecule drugs bind and inhibit the disease-causing activity of their (typically intracellular) protein targets, Gate Bio instead attacks harmful extracellular proteins by eliminating them at their very root: right where they are produced and secreted from the cell. The secretion of ‘bad-actor’ proteins can drive conditions like neurodegeneration, autoimmunity, cancer, and more: what if we could design small molecules to stop them (“gate” them) from being secreted in the first place—before they even have a chance to cause disease?

To do this, the founders at Gate Bio had a clever idea: to exploit the biology of the single, shared channel through which all ~4000 secreted human proteins must make their journey out of the cell. To visualize this mechanism, go all the way back to high school biology and recall that squiggly, ribosome-lined organelle called the endoplasmic reticulum (ER). Remember learning that it functions as the cell’s manufacturing and transportation apparatus? Well, this is because getting important secretory proteins (peptide hormones, receptors, cytokines, etc) across the cell’s membrane (a lipid bilayer) from inside the cell to outside is no easy task—and nature has evolved a tightly choreographed dance to make this happen. Central in this sequence is the ER, and specifically a channel within the ER called the secretory translocon, through which all newly synthesized secretory proteins coming off a ribosome must pass in order to enter the ER, fold properly, and ultimately exit the cell. 

As the scientific community gained greater insight into the structure and function of the secretory translocon, Gate Bio’s founders began creatively designing Molecular Gates to bind this translocon and specifically block disease-causing proteins (but not healthy proteins) from exiting the channel. Once a disease protein is ‘gated’ from exiting the channel, it has nowhere to go, and then—as if in a stroke of elegant science fiction!—it gets degraded by the cell’s already existing, natural cleanup machinery. Behold!

If Molecular Gates could be engineered for many high-value targets, they could represent a massive new drug class for extracellular protein targets, with a fundamentally new mechanism of action in the cell—a rare feat in biotech. This vision got us excited, in part because we’ve seen other novel drug classes in recent years (e.g. molecular glues, PROTACs, splice modulators, and more), and each new class has proven that new mechanisms of action can unlock previously inaccessible targets that are important in human disease. Inventing a new modality is also one of the best ways to endow an otherwise lean biotech startup team with a massive moat. 

At a16z, we love platform biotech companies, and Gate Bio’s platform has a particularly unique feature that we couldn’t resist. Molecular Gate medicines, no matter the target, share a common mechanism of action: gating that secretory translocon. This means that every technology that gets built at the company, every problem solved, and insight uncovered—actually makes all our future programs smarter. Gate Bio is building the platform to screen, design, systematically characterize, and optimize Molecular Gates. And it’s truly a self-reinforcing, always-learning engine that is getting better every day.

An inventive ensemble of builders

I have known Jordi Mata-Fink, cofounder and CEO of Gate Bio, for nearly two decades. We went to college at Stanford together, and were even lucky enough to live in the same hallway of the same dorm community (shout out to “FroSoCo” nerds everywhere)! What I remember most from then was Jordi’s massive smile, his excitement when describing an engineering problem, and the way in which people gravitated towards him. Our paths crossed again when we were both in grad school at MIT, and then Jordi subsequently joined a biotech venture incubator in the Boston ecosystem where he helped build and lead several new companies. He has always loved both science and people, and so when he called to say he was starting a biotech company and raising Seed financing, I knew I wanted to be involved.

Raman Talwar (Gate Bio cofounder) and I first met in the context of another exciting company that he helped start a few years ago—where I learned that he has an infectious “Yes, why not?” personality that always makes people want to try and jump even higher. Raman is endlessly and authentically curious, a quality which, when combined with his personal magnetism, makes him a hub for the creative synthesis of new ideas and (perhaps more importantly for a young company) the creative assembly of new people.

And finally, it’s been a joy to work with Pat Sharp, cofounder and the original chemistry brains behind the Gate Bio operation. Pat co-led academic work on chemically perturbing the secretory translocon at UCSF and then did a tour of duty in big pharma at Merck before jumping into Gate to lead the development of our chemistry and experimental science platform. He is super smart, wonderfully kind, and explains even the most complex chemistry in a soothing Australian accent.

I suspect the founders would say that they are most proud of the amazing team they have recruited around themselves. The Gate Bio team – still small but mighty – is a special ensemble of talent. They are deeply motivated by patient experience, and willing to tread in new waters. They aren’t afraid to build new tools and new ways of measuring the impact of a Molecular Gate, but are also keen to learn from the experience of previously ‘new’ modalities. I can feel the urgency of ‘patients are waiting’ in every interaction with this team, and it is thus such a privilege to be co-leading Gate Bio’s Series A financing and joining their board. We are also thrilled to be working with great friends at Versant Ventures, GV, and ARCH. Please reach out if you’re interested in joining this team of pioneers!

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