A prodrug is an inactive compound that is metabolized in the body, thus acting like a drug after administration and can be used to enhance the absorption and distribution of a particular drug. That is precisely what Johns Hopkins Medicine scientists have achieved, who have developed a prodrug from an anticancer drug that did not reach clinical practice due to its toxicity, and that attacks cancer cells without harming healthy tissues.
These researchers have revamped a cancer-fighting drug so that it releases its payload only in a specific area of the body. The prodrug they have designed, called DRP-104 (sirpiglenastat), is now being tested in patients with advanced solid tumors in phase I/II clinical trials in the United States, but studies in mice published in Science Advances have shown that it is capable of preferentially killing cancer cells without harming healthy cells.
“Our goal was to modify an old cancer drug that had shown great efficacy, but was too toxic, especially to the gut, to be developed clinically. To do this, we use a prodrug approach. What is unique about our approach is that we used a novel chemical design to create a prodrug that was simultaneously bioactivated in cancer cells, but bioinactivated in healthy tissues such as the intestine. This preferential targeting of the payload to cancer cells now allows this effective class of drugs to be safely retested in people,” said study author Barbara Slusher, director of the Johns Hopkins Drug Discovery Program and professor of neurology, pharmacology and molecular sciences, psychiatry, neuroscience, medicine and oncology at the Johns Hopkins University School of Medicine.
Eliminate the tumor without causing intestinal toxicity
The prodrug modified by these scientists takes advantage of a characteristic of cancer cells, which is their need for the amino acid glutamine, which is key to the formation of proteins, lipids, nucleotides and energy. Fast-growing cancer cells use a large amount of glutamine, a phenomenon known as “glutamine addiction,” but other healthy cells with rapid turnover, such as those lining the intestine, also rely on glutamine.
“We used a novel chemical design to create a prodrug that was simultaneously bioactivated in cancer cells, but bioinactivated in healthy tissues such as the intestine”
Rana Rais, associate professor of neurology and pharmacology and co-author of the study, explained that “DRP-104 is a prodrug of the glutamine-mimicking drug DON (6-Diazo-5-Oxo-L-norleucine), which inhibits multiple enzymes that use glutamine in cancer cells. Many early studies of DON showed that it was very effective in people and mice, but its development was halted due to its toxicity to normal tissues, especially the intestine.”
Slusher, Rais, and their team decided to make chemical modifications to DON: “We added chemical groups, called promoters, to DON that inactivated it in the body until it reached the tumor, where the promoters were cleaved by enzymes that are abundant in the tumor, but not in the gut,” Slusher said. “This specific prodrug design made DON target its intended destination (tumor) and have less of an impact on healthy cells elsewhere.”
These researchers gave the original drug DON and the improved drug DRP-104 to mice that had been implanted with tumors, and in those that received DRP-104 they found 11 times more active drug in the tumor compared to the gastrointestinal tract (intestine). ). Although both drugs completely eliminated the tumor, DON caused more intestinal toxicity in the animals than DRP-104.
Slusher and study co-authors Rana Rais, Pavel Majer and Jonathan Powell co-founded a biotechnology company, Dracen Pharmaceuticals Inc, which has licensed this new prodrug for clinical development and has already begun preliminary human studies. In addition, Slusher has stated, his Johns Hopkins Drug Discovery laboratory is looking for other drugs that have failed clinical trials due to their toxicity with the goal of using this same prodrug design for drugs intended to treat other health problems.
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