Out of CRISPR pioneer David Liu's lab comes a small molecule play targeting exosites — and it's raised a modest $25M to push toward clinic
David Liu may be best known as a CRISPR trailblazer behind Editas Medicine, Beam Therapeutics and Prime Medicine. But more than six years ago, he worked with a student from his Harvard lab and then-colleague Alan Saghatelian on a much different project: developing a small molecule inhibitor of insulin-degrading enzymes.
For close to six decades, scientists had theorized that blocking the enzyme can salvage enough insulin to treat Type 2 diabetes. The problem is that IDE, despite its name, doesn’t just degrade insulin; it also gets rid of glucagon, which is something you actually don’t want a lot of for a diabetic patient. Traditional drug discovery methods couldn’t solve the need to shut down one activity while leaving the other alone.
The solution Liu and Saghatelian’s team found was on the enzyme itself.
Rather than drugging the active site, they realized that they could hit the exosite — a far away site where insulin actually comes to dock — and achieve the selective inhibition.
The student, Juan Pablo Maianti, stayed with Liu at the Broad for a postdoc to develop the idea before co-founding and becoming employee No. 1 at Exo Therapeutics. A seed round and two years later, the Cambridge, MA-based biotech is pushing ahead on four preclinical programs with $25 million in Series A cash from Newpath Partners, Novartis Venture Fund, CRV and 6 Dimensions Capital.
What the 2014 paper established is now just one of four pillars at Exo, said CEO Michael Bruce, namely the ability to discover an exosite on an enzyme. Unlike allosteric sites — the binding of which can indirectly impact the active site — exosites are typically involved in some function of the protein, opening up a more specific way to deal with pleiotropic enzymes.
“I read somewhere that 672 enzymes make up the entire drug industry, the multi-trillion dollar drug industry,” Bruce, who came on board in February, told Endpoints News, “but there are something like 10,000 enzymes that are thought to have a role in human disease.”
Maianti and the eight other staffers who joined him also built a platform that can make the enzymes or enzyme complexes for them to experiment with; brought in DNA-encoded libraries to start a screening effort; and nailed down the initial targets in oncology and inflammation.
Down the road, though, Bruce sees the company applying its tech to neuroscience, cardiovascular and metabolic, plus a range of diseases.
They will all be drawing from a whole new infrastructure that Exo has constructed from scratch — one that, while reminiscent of what he’s experienced during his years at Pfizer, doesn’t feel any less cutting-edge than the CRISPR and microbiome tech he’s seen over several stints at biotech startups.
“To me there’s this confluence of technologies starting with cryo-EM going to molecular modeling going to DNA-encoded libraries going to protein synthesis — all of these things I think now allow us to really explore some of these enzymes and enzyme complexes in new ways,” he said.
Bruce expects to steer Exo’s first drugs into the clinic in the next couple of years, at which point he also envisions exosite conferences starting to be a thing as the science develops.
At least a trio of respected scientists are similarly convinced it would. Stuart Schreiber of the Broad, Ben Cravatt at Scripps and Ben Ebert of Dana-Farber have all joined Liu and Saghatelian (who’s now at Salk) on the scientific advisory board as Exo plans to double its size.