Startup Expedition Medicines sets out to learn nature’s rules for binding elusive proteins

Thousands of proteins are known to cause disease, but while the biological activity of these proteins is understood, how to administer and modulate them with a drug is not. Nature still has ways to link molecules to these elusive proteins, said Molly Gibson, co-founder and CEO of startup Expedition Medicines. What scientists lacked was the ability to decipher them.

Expedition, based in Cambridge, Massachusetts, uses artificial intelligence to study proteins and learn the chemical rules of nature, Gibson said. The young company, created by the founder of startup Flagship Pioneering, came out of stealth to discover and develop new small molecule drugs for elusive protein targets.

The bonding of a molecule to a protein is a chemical reaction that forms a strong connection between them called a covalent bond. Proteins considered nondrugable have smooth surfaces or shallow pockets that make it difficult for a potential drug to form this bond. The search for new drugs has always involved screening a library of molecules against a set of targets to see what binds. This approach presents challenges because the easy targets are already reached. So, to make research productive, drug hunters need larger libraries to get more results.

The data analyzed by Expedition is proprietary. Expedition’s research is based on a chemoproteomics technology platform that analyzes interactions between proteins and small molecules. The technology extracts small molecules from the startup’s proprietary library and tests them at more than 20,000 sites in the human proteome, generating data on the protein’s specific small molecule and 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 capable of binding to proteins with shallow pockets or smooth surfaces.

“Learning from nature, we were able to identify that across the proteome, on the surface of proteins, there are all these latent catalytic sites that, when viewed from a new angle, 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, which would have been impossible otherwise,” Gibson said.

Analysis by shipping technology gives a reading, a quantitative score of target engagement between the small molecule and a specific amino acid on the protein, Gibson said. This score is directly linked to the formation of the chemical bond. Because this data is aligned with generative AI and quantum chemistry, Expedition scientists believe the company will be able to apply these new ways of examining small molecules and proteins for targets that have not been addressed before, she said.

Expedition was founded three years ago. Flagship has trained other startups that use the technology to analyze proteins. ProFound Therapeutics emerged in 2022 with technology that searches for new drugs by exploring previously unknown 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 the expedition is different in that it doesn’t analyze the proteome to discover new biology. What the startup is trying to do is target targets whose biology is already known, but whose chemistry to bind these targets is not. The Expedition team includes two of the founders of Vividion Therapeutics, a startup whose proteome analysis platform technology has discovered small molecules capable of binding to elusive targets. In 2021, Bayer acquired Vividion for $1.5 billion upfront.

There are other startups developing drugs to form 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 stage clinical development with a small molecule inhibitor of a solid tumor target called AKT1. Enlaza Therapeutics launched a platform last year to develop biologic drugs that form covalent bonds with elusive cancer targets.

Expedition is backed by the usual $50 million that Flagship provides to its companies at launch. With the startup now out of reach, fundraising will continue, Gibson said. The specific targets of the Expedition’s research remain confidential. Gibson said Expedition drug modalities are developing bifunctional trabeculum inhibitors, activators and degraders. The platform technology is indication agnostic, but Gibson said the preclinical pipeline currently focuses on immunology and oncology. A partnership could bring the startup to other therapeutic areas.

Expedition already has a partnership with Pfizer focused on prostate cancer. This alliance is part of a deal Flagship struck with the pharmaceutical giant in 2023. The deal 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 potential in the Expedition platform to solve challenges related to hard-to-treat targets, particularly in cancer. The partnership with Expedition is a multi-target agreement funded by Pfizer.

“They brought us the targets, those are their targets,” Gibson said. “We generate chemistry.”

Image from Expedition Medicines