UF researchers discover first-of-its-kind compound to target lung cancer cells

JUPITER, Fla. — Inside cells, a large family of proteins known as heat shock proteins function like attentive mother hens. They shepherd less sophisticated proteins across cell membranes and help proteins assume the shape they need to function correctly.

But rapidly dividing cancerous cells take advantage of this cellular quality control system, hijacking heat shock proteins to help them survive stress and stay alive. That means developing a drug that targets these proteins could be a way to thwart cancer.

For more than a decade, the lab of organic chemist Eli Chapman, Ph.D., a professor in the Department of Pharmacology & Therapeutics working at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, has been dedicated to a singular quest: Targeting a specific heat shock protein that drives lung cancer.

Using an innovative technique that allowed them to screen hundreds of molecules at once, Chapman’s lab reached a milestone: The scientists discovered the first compound that effectively targets the protein, GRP78, and could ultimately be developed as a drug for humans. The findings were published recently in Angewandte Chemie International Edition.

“Our molecule is the very first example of a highly specific molecule that only targets GRP78,” said Chapman, a member of the UF Health Cancer Institute’s Cancer Targeting and Therapeutics research program. “I’m hoping we can push these molecules toward the clinic and learn a lot about how these proteins drive cancer biology and cancer transformation.”

GRP78 is one of a 13-member family of heat shock proteins. Studies have shown GRP78 levels are about four times higher in lung cancer patients’ tissue than in that of healthy patients. Higher levels are linked with worse outcomes, mutations that drive cancer and drug resistance.

Despite treatment advances over the past two decades, the five-year survival rate for lung cancer remains about 25%.

Over the years, other researchers have developed compounds to target five sites on GRP78, with mixed effectiveness. The one developed by Chapman’s lab, which they call compound 12, is the first to target a small, claw-like pocket on the protein. The claw allows other proteins to attach and undergo proper folding that ensure cells function normally.

When graduate student Andrew Ambrose, then a graduate student in the Chapman lab, proposed targeting this exact spot, Chapman was a bit skeptical.

“Because these proteins have remained largely unchanged across species over millions of years of evolution, I wasn’t sure it was going to work,” Chapman said. “But it worked brilliantly. We’re the first to specifically and intentionally target that pocket.”

Chapman’s team, led by graduate student Xiaoyi Zhu, used a method, called direct-to-biology, that allowed them to rapidly test large batches of molecules at once to measure their potency, selectivity and toxicity. The team ultimately screened nearly 700 molecules.

Compound 12 was 100 to 200 times more selective for GRP78 than other HSP70s and much more selective than other compounds developed to target heat shock proteins, Chapman said. Not only did it strongly and selectively inhibit GRP78, it also killed lung cancer cells directly by inhibiting GRP78 in lab testing and in mice, the team found.

“Our compound is interestingly selective for certain lung cancers, which is really exciting to us,” Chapman said.

Those lung cancers are typically ones driven by KRAS mutations, the most common cancer-causing genetic mutation in humans. Because of its effects on the central machinery of cells, it’s possible that targeting GRP78 may have an advantage over other drugs that target such mutations.

Now, the researchers are working to refine compound 12’s structure, as well as developing compounds to target each of the HSP70s.

“I think we’re going to be able to find molecules for every HSP70 and actually parse out what they’re doing in different cell lines,” Chapman said.

Ultimately, that could allow the researchers to develop new biomarkers to guide treatment approaches based on specific mutations.

Chapman holds about a dozen patents for related molecules. His lab plans to further test the compounds in animals, as well as in cell populations provided by the National Cancer Institute’s specialty oncology collection.

Chapman collaborates with UF Health Cancer Institute members and co-authors Aikseng Ooi, Ph.D., a biochemist with expertise in cancer informatics, and molecular toxicologist Donna Zhang, Ph.D. The research was funded by UF startup funds and the National Cancer Institute through the Cancer Institute’s Team-based Interdisciplinary Cancer Research Training (TICaRT) Program. Lewis Alexander, a trainee in Chapman and Zhang’s labs and a publication co-author, is a fellow in the TICaRT program.