Feb. 25, 2026
For years, cancer researchers have been trying to block molecules that are involved in several cancers. The molecules — enzymes known as trypsins — help cancer cells invade healthy tissue and encourage tumor progression.
Evette S. Radisky, Ph.D., a cancer biologist at Mayo Clinic in Florida, previously found that one trypsin, called mesotrypsin, plays a role in breast, prostate, pancreatic and lung cancers. Like other enzymes, the molecule has an active site that initiates reactions with other molecules. Researchers have tried to block the active site but haven't been able to do so selectively.
Recently, however, Dr. Radisky's lab uncovered an unexpected vulnerability in a "cryptic pocket" of the enzyme.
"The cryptic pocket is separate from the active site, and we found that blocking it has a similar effect of locking the enzyme in an inactive state," says Dr. Radisky, principal investigator of the study that appeared in Science Advances. This finding could pave the way for new cancer therapeutics with fewer off-target effects.
A mystery in the data
"It was a serendipitous finding," says Mathew A. Coban, the study's lead author, of the pocket's discovery. As a research technologist in the Radisky lab and a master's degree student at Mayo Clinic Graduate School of Biomedical Sciences, Coban had been using X-ray crystallography to study the structure of mesotrypsin.
The complex technique, which records scattered X-rays as shadows, can describe the overall folds of amino acids in the enzyme and suggest complementary molecules that fit like a puzzle. While reviewing the X-ray crystallography results, Coban noticed something unusual — a segment of the enzyme that didn't look like it belonged. The research team suspected an error in the data and set the results aside.
Coban later reviewed the data and wondered if there was more to discover about the segment. He began looking for alternate nooks in the mesotrypsin enzyme and found the cryptic pocket adjacent to the active site. The pocket opened at moments when mesotrypsin adopted a stable, inactive form.
This discovery set the team in a new direction. "We thought, 'if the pocket is present some of the time, maybe it could be a therapeutic target,'" Coban says. "So we started looking for a molecule that could bind at that site and lock the enzyme in its inactive state."
Finding a drug that binds
The team enlisted the help of Thomas Caulfield, Ph.D., a former Mayo researcher and drug discovery expert. Dr. Caulfield performed high-throughput virtual screening of numerous compounds. The team identified a single molecule that could bind in the cryptic pocket and inhibit the activity of mesotrypsin.
Significantly, the researchers note, that molecule blocks mesotrypsin selectively, without affecting other trypsins. This selectivity could result in reduced toxicity or fewer side effects for the patient. The finding also means that other cryptic pockets may exist in other trypsin enzymes related to cancer, presenting new potential drug targets.
Looking ahead
Although the work is still in its early stages, the implications are significant. Researchers tried unsuccessfully to target trypsin for decades. The discovery of a new binding site — and proof that a molecule can block the mesotrypsin enzyme — fundamentally changes the landscape.
"Based on the structural information of mesotrypsin that we have, we've been able to do more computational prediction to identify additional, more-potent compounds that we're now testing in the laboratory," says Dr. Radisky. "Our next steps will be to start testing how well our candidate drug molecules bind in the cryptic pocket and block cancer invasion and metastasis in models of disease."
For more information
Coban M, et al. Discovery of an autoinhibited conformation in mesotrypsin reveals a strategy for selective serine protease inhibition. Science Advances. 2025;11:eadu9129.
Mayo Clinic Graduate School of Biomedical Sciences.
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