Thousands of proteins are known to cause disease, but while the biological activity of these proteins is understood, there is no known way to target and modulate them with a drug. Nature still has ways to attach molecules to these elusive proteins, said Molly Gibson, co-founder and CEO of the startup Expedition Medicines. What scientists have lacked is the ability to decipher them.
Expedition, based in Cambridge, Massachusetts, uses artificial intelligence to study proteins and learn nature’s chemical rules, Gibson said. The young company, formed by startup creator Flagship Pioneering, has emerged from stealth discover and develop new small molecule drugs for hard-to-reach protein targets.
The binding of a molecule to a protein is a chemical reaction that forms a strong connection between them called a covalent bond. Proteins that are considered non-drug have smooth surfaces or shallow pockets that make it difficult for a potential drug to form that bond. Historically, the search for new drugs has arisen from screening a library of molecules against a set of targets to see what binds. That approach poses challenges because the easy targets have already been achieved. So for the search to be productive, drug hunters need larger libraries to get more results.
The data Expedition analyzes is proprietary. Expedition’s research is powered by a chemoproteomics platform technology that analyzes interactions between proteins and small molecules. The technology takes small molecules from the startup’s proprietary library and screens them at more than 20,000 sites across the human proteome, generating data on the small molecule and protein-specific amino acids. From there, Expedition uses generative AI and quantum chemistry to learn the rules of chemistry: how chemical bonds form on the surface of proteins. This approach allows Expedition to identify molecules that can bind to proteins with shallow pockets or smooth surfaces.
“By learning from nature, we’ve been able to identify that across the proteome, across the surface of proteins, there are all these latent catalytic sites that, if you look at it from a new direction, a new perspective, a new view of chemistry, we can form a reaction and form a chemical bond between a small molecular protein and bind in these areas that otherwise would have been impossible,” Gibson said.
Analysis using Expedition’s technology produces a readout, a quantitative score of the target engagement between the small molecule and a specific amino acid in the protein, Gibson said. That score correlates directly with the formation of the chemical bond. Because that data is aligned with generative AI and quantum chemistry, Expedition scientists believe the company will be able to apply these new ways of observing small molecules and proteins for goals that haven’t been addressed before, he said.
The expedition was founded three years ago. Flagship has formed other startups that use technology to analyze proteins. ProFound Therapeutics emerged in 2022 with a technology that searches for new drugs by exploring previously undiscovered proteins beyond the 20,000 proteins identified by the Human Genome Project. Prologue Medicines was launched last year to explore the viral proteome. Gibson said Expedition is different because it doesn’t analyze the proteome to discover new biology. What the startup is trying to do is address targets whose biology is already known, but the chemistry to bring these targets together is not. The Expedition team includes two of the founders of Vividion Therapeutics, a startup whose proteome analysis platform technology discovered small molecules that can bind to elusive targets. In 2021, Bayer acquired Vividion for $1.5 billion up front.
There are other startups developing drugs aimed at forming covalent bonds with elusive drug targets. Nexo Therapeutics launched in 2023 with two technology platforms focused on the development of novel small molecule cancer drugs. Terremoto Biosciences has reached early clinical development with a small molecule solid tumor inhibitor called AKT1. Enlaza Therapeutics launched last year with a platform to develop biologic drugs that form covalent bonds to hard-to-reach cancer targets.
Expedition is backed by the usual $50 million that Flagship offers its companies at launch. Now that the startup is no longer hidden, fundraising will continue, Gibson said. The specific objectives of the Expedition investigation remain undisclosed. Gibson said Expedition drug modalities are developing bifunctional inhibitors, activators and degraders. The platform technology is indication-agnostic, but Gibson said the preclinical portfolio is currently focused on immunology and oncology. The partnership could take the startup into other therapeutic areas.
Expedition already has a partnership with Pfizer focused on prostate cancer. This alliance is part of an agreement that Flagship entered into with the pharmaceutical giant in 2023. The agreement gave Pfizer the opportunity to explore all of Flagship’s platforms and decide which ones fit its areas of interest. Gibson said Pfizer saw the Expedition platform offered the potential to solve challenges in hard-to-treat targets, specifically cancer. The partnership with Expedition is a multi-target agreement funded by Pfizer.
“They brought us the targets, they are their targets,” Gibson said. “We’re building the chemistry.”
Image from Expedition Medicines
