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Drug Discovery

Exo Therapeutics raises $78 million to target enzyme exosites with small molecules

The startup is based on work from the labs of chemists David Liu and Alan Saghatelian

by Ryan Cross
October 5, 2021

A crystal structure showing an inhibitor binding to insulin-degrading enzyme.
Credit: Protein Data Bank ID 6BYZ
An insulin-degrading enzyme inhibitor discovered in David Liu’s lab.

Exo Therapeutics raised $78 million in series B financing to develop a new strategy for drugging enzymes. Many drugs work by blocking target enzymes’ active sites, which perform reactions like cleaving or phosphorylating a peptide or protein substrate. But directly blocking the active site doesn’t work well for all enzymes, so Exo has developed an indirect approach to inhibit enzymes by blocking their so-called exosites instead.

Exosites are binding pockets or grooves that hold a substrate in place while the enzyme’s active site performs a reaction on that substrate, Exo CEO Michael Bruce explains. His startup hopes to design small molecules that target exosites and disrupt or block substrates from binding to them, providing an alternative to targeting the active site.

There are a few reasons why scientists would want to drug an exosite rather than an active site, Bruce says. For one, some enzymes have active sites that have proven difficult to drug because the natural substrate binds so tightly to the active site.

And some families of enzymes have active sites that are nearly identical to each other, making it hard to design a drug that binds only to a specific one. That selectivity challenge often arises with a common class of drug targets called kinases, he says. By targeting kinases’ exosites, Exo may be able to design drugs that are more selective and have fewer side effects than some existing kinase inhibitors that target active sites.

Exosites could also provide a new way to drug pleiotropic enzymes, which perform more than one function. Insulin-degrading enzyme, for example, breaks down both insulin and glucagon—two molecules that have opposing effects. Researchers developing drugs to treat Type 2 diabetes have long sought inhibitors that block only the enzyme’s insulin-degrading ability, but targeting the enzyme’s active site prevents its ability to break down both insulin and glucagon.

In 2019, David R. Liu at the Broad Institute of Harvard and MIT published a paper in Nature Chemical Biology revealing his lab’s use of DNA-encoded libraries to discover compounds that bind to an exosite to prevent insulin binding while preserving glucagon activity. The work, which was led by Liu’s then-PhD student Juan Pablo Maianti, formed the basis of Exo, which was founded in 2018 with Alan Saghatelian at the Salk Institute for Biological Studies. The startup raised an initial $25 million in series A financing in December 2020.

Bruce says that Exo is not currently developing a drug for insulin-degrading enzyme because diabetes drug development is “a tricky place” for a small biotech company. But he is excited about using Liu and Maianti’s work on DNA-encoded libraries as the basis for finding compounds that target exosites on other enzymes. The new financing will be used to advance four preclinical programs for small-molecule drugs—three for cancer and one for autoimmune disease and inflammation. “We are looking to go into the clinic in the next couple of years,” Bruce says.


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