Augmented drug preferentially eliminates cancer cells but does not damage healthy cells

Augmented drug preferentially eliminates cancer cells but does not damage healthy cells

Researchers at Johns Hopkins Medicine have redesigned a cancer drug to better attack cancer cells and leave healthy tissue unharmed. Scientists have called this type of targeted approach a “prodrug” –; a drug designed to deliver its payload to a specific area of ​​the body and no other area. The Johns Hopkins-discovered prodrug called DRP-104 (sirpiglenastat) is in early-stage clinical trials in people with advanced solid tumors. The newly published studies in mice show that the boosted drug preferentially eliminates cancer cells but does not harm healthy cells.

A report on their experiments will be published November 16 in Science Advances.

"Our goal was to modify an old cancer drug that had shown robust efficacy but was too toxic, particularly to the gut, to be developed clinically. To do this, we used a prodrug approach. What is unique about our approach is that we used a novel chemical design to create a prodrug that would simultaneously bioactivate in cancer cells but in healthy tissues such as the gut “This preferential targeting of the payload to cancer cells now makes it possible to safely reevaluate this potent class of drugs in humans,” says study author Barbara Slusher, Ph.D., MAS, director of the Johns Hopkins Drug Discovery Program and professor of neurology, pharmacology and molecular sciences, psychiatry, Neuroscience, Medicine and Oncology at Johns Hopkins University School of Medicine.

The newly modified prodrug exploits a common trait of cancer cells: an insatiable appetite for an amino acid called glutamine, which is a crucial building block for proteins, lipids and nucleotides, as well as energy production. Fast-growing cancer cells consume an enormous amount of glutamine, a phenomenon called "glutamine addiction," but other healthy cells with rapid turnover, such as those lining the intestines, also rely on glutamine.

DRP-104 is a tumor-targeting prodrug of the glutamine mimetic called DON (6-diazo-5-oxo-L-norleucine), which inhibits multiple glutamine-utilizing enzymes in cancer cells. Many early studies of DON showed that it was highly effective in humans and mice, but its development was halted due to its toxicity to normal tissues, particularly the intestines.

Rana Rais PhD, study co-author and associate professor of neurology and pharmacology, Johns Hopkins Medicine

Drug Discovery E-Book

Compilation of the top interviews, articles and news from the last year. Download a free copy

Development of this promising class of drugs did not resume until Slusher, Rais, and their team decided to chemically modify DON.

“We added chemical groups called pro-units to DON that made it inactive in the body until it reached the tumor, where the pro-units were cut off by enzymes that are abundant in the tumor but not in the intestine,” says Slusher, who is a member of the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy. “This specific prodrug design made DON targeted to its intended target (tumor) and has less impact on healthy cells elsewhere.”

For the new study, researchers gave mice that had been implanted with tumors the original DON drug and the souped-up DRP-104 drug. In mice that received DRP-104, researchers found 11 times more drug in the tumor than in the gastrointestinal (gastrointestinal) tract. Both drugs completely eradicated the tumor, but DON caused more intestinal toxicity in the mice than DRP-104.

Slusher and study co-authors Rana Rais, Pavel Majer and Jonathan Powell co-founded a biotechnology company, Dracen Pharmaceuticals Inc, which licensed this new prodrug for clinical development. DRP-104 is in Phase I/II clinical trials at sites across the United States, including the Johns Hopkins Kimmel Cancer Center, for people with advanced-stage solid tumors. Slusher says her Johns Hopkins Drug Discovery lab is also actively looking for other drugs that have failed in clinical trials due to toxicity issues. They hope to apply the same prodrug design to drugs for other diseases.

Source:

Johns Hopkins Medicine

Reference:

Rais, R., et al. (2022) Discovery of DRP-104, a tumor-targeting metabolic inhibitor prodrug. Scientific advances. doi.org/10.1126/sciadv.abq59.

.