December 16, 2020
Michael Bruce, Ph.D., has worked for the likes of Pfizer and CRISPR Therapeutics, but now he’s the CEO of what he believes will be the future in medicine: Exo Therapeutics. The company raised $25 million (PDF) in series A funding to back a pipeline of drugs that bind their enzyme targets at their exosites. The goals are to create better medicines without harmful side effects and to hit targets that were previously considered undruggable.
“People asked me, ‘Why are you going to a small molecule company?’” Bruce said. “Interestingly enough, two-thirds to three-quarters of all drugs that are approved are still small molecules, the FDA and other regulatory bodies are very clear on how to get a small-molecule drug approved, and I’m convinced that it’s a really cool idea that is very generalizable.”
Based on research from the labs of David Liu, Ph.D., and Alan Saghatelian, Ph.D., Exo’s approach results in drugs that bind to enzymes’ exosites, rather than their active sites. By combining computational biology, protein engineering and DNA-encoded libraries, Bruce believes Exo Therapeutics can create drugs that target the 9,400 enzymes that can’t be drugged traditionally, including those that play a role in cancer and inflammation.
Historically, Bruce said, the industry has developed drugs that target the active site, an approach that has worked for nearly 700 of the 10,000 enzymes thought to have a role in human disease. But many remain untapped because they can’t be drugged in this traditional manner for three reasons.
The first is that traditional drugs can’t compete with other substrates at the active site. Second, a drug’s effects may reach beyond its target enzyme, affecting other members of that enzymatic family and leading to side effects. Finally, many enzymes are pleiotropic, which means they control a variety of functions, so shutting down the enzyme completely by binding to that active site prevents it from serving its other essential functions.
“It's kind of like drugging the switch of a light instead of the light socket,” Bruce said. “When you drug the switch you also shut down all of the activities as well.”
Exosites are a better alternative because they are not close to the active site, which means there is less competition for binding than there would be in the active site. Exosites are more specific to enzyme-driven enzyme complexes, which avoids the cascading familial effect. Finally, targeting an exosite means scientists can target an enzyme’s specific activity without blocking its other functions.
Bruce provides the example of the longtime battle to drug the insulin-degrading enzyme studied by Liu, which degrades not only insulin but also glucagon. Shutting it down means leaving insulin in the body, which is beneficial, but also leaves glucagon untouched, which is a problem for diabetic patients. If the exosite is targeted, the enzyme can be controlled to only degrade glucagon by inhibiting the docking of insulin while leaving activity against glucagon untouched.
“You're not actually blocking the specific control site, which shuts everything down; you're finding a place where a substrate is coming in, and you're putting a drug there,” Bruce said. “You're targeting that interaction, and so you're affecting the whole thing without actually affecting that active site, which gives us a real selectivity advantage.”
In the next year, the new financing, drawn from Newpath Partners, Novartis Venture Fund, CRV and 6 Dimensions Capital, will enable Exo Therapeutics to identify more exosites for drug targets and advance its current set of programs toward developing candidates for clinical trials within the next few years.
“It's a year of building and it's a year about chance for us,” Bruce said.
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