Edward Chouchani, PhD
Professor, Harvard Medical School, Dana-Farber
New and more effective treatments for autoimmune and inflammatory diseases may soon be within reach, thanks to a new technology developed by scientists from Dana-Farber Cancer Institute and Stanford University.
Edward Chouchani, PhD, Professor of Cancer Biology at Dana-Farber and Howard Hughes Medical Institute (HHMI) Investigator, and Nathanael Gray, PhD, Professor of Chemical and Systems Biology at Stanford, have developed chemical “tags” that act like molecular beacons to locate disease-causing proteins inside cells. This approach, which has been licensed to a biotechnology company, fuels an advanced screening platform that combines small-molecule chemistry with machine learning to discover drugs for immune system disorders.
Turning Off the Body’s Inflammatory Response
When the immune system mistakenly attacks healthy tissue—as in autoimmune conditions like lupus or rheumatoid arthritis—it causes chronic inflammation and tissue damage. Yet more than 95 percent of the proteins that drive these diseases are considered “undruggable,” meaning there are no known medicines that can effectively block their activity.
To tackle this challenge, Chouchani, Gray, and their colleagues developed a two-step discovery process. First, the researchers used cysteine phosphate tags—chemical markers that attach to amino acids within proteins—to create a detailed map of regulated protein pockets across the proteome (the complete set of proteins in a cell). This allowed them to identify hundreds of new functional protein pockets involved in the body’s inflammatory response
“We were able to follow nature to see where metabolites are used to regulate protein function.
Edward Chouchani, PhD
Next, they screened small-molecule compounds—tiny drug candidates designed to interact with proteins—to see which could bind and switch off these targets, thereby calming the immune system’s overreaction. These small molecules are called covalent inhibitors, a class of compounds that form a tight, irreversible bond with their protein targets. Because these molecules “lock on” to their targets, they can be more potent and longer-lasting than many standard drugs.
“We were able to follow nature to see where metabolites [small molecules cells make to help generate energy] are used to regulate protein function,” says Chouchani. “We use this as a shortcut to develop drugs that target those same sites—an approach we’re very hopeful about.”
These efforts were supported by the Dana-Farber Accelerator Program, HHMI, the Mark Foundation for Cancer Research, and the V Foundation.
Building on Discoveries in Cancer and Metabolism
Chouchani and Gray’s drug-discovery process for treating autoimmune conditions builds on years of research linking metabolism to cancer and other diseases.
In 2020, the team published a Cell paper describing Oximouse, a research platform that identifies how proteins are regulated by the amino acid cysteine, which helps control energy use in cells.
Two years later, they reported in Nature Chemical Biology that Oximouse could identify new ways to target creatine kinases—enzymes that provide the quick energy cancer cells need to grow—offering new leads for cancer therapy.
More recently, in another study that appeared in Nature Chemical Biology, they identified a new spot on an immune‑regulating protein called SHP1 that can be switched off with specially designed small molecules. By calming this protein’s activity, researchers were able to reduce inflammation in immune cells, showing how this strategy could open the door to new treatments for many hard‑to‑target diseases.
“This work is unique in that the chemical starting points were discovered using chemoproteomic screens [a technique for finding which small molecules stick to which proteins] of covalent fragments,” Gray explains. “It allowed us to screen a small number of compounds against the entire proteome rather than relying on known binders.”
Carrying the Science Forward
Now the biotechnology company that licensed this innovation is moving the technology development forward. They have built a library of small-molecule compounds that can be quickly matched to disease-related proteins.
To date, thousands of molecules have been screened. Although the work is still in its early stages, researchers are optimistic that it could lead to faster, more precise treatments for autoimmune and inflammatory diseases—and potentially many other conditions that have long eluded drug developers.
Team Members: Edward Chouchani, PhD, Nathanael Gray, PhD.
Team Members
Nathanael S. Gray, PhD
Professor of Chemical and Systems Biology, Co-Director of Cancer Drug Discovery, Stanford Medicine
Former Principal Investigator, Dana-Farber
