Nobuhide Ueki in the labSTONY BROOK UNIVERSITYThe drug: Researchers have found a new way to modify cell-killing agents to make them selectively poison cancer cells, while avoiding healthy cells, according to a paper published today (November 5) in Nature Communications. The researchers deactivated a toxic agent, puromycin, by adding an acetylated lysine residue to it. The resulting compound, called Boc-KAc-Puro, is a prodrug—the compound is biologically inactive until it interacts with enzymes produced by the cancer cells it targets. The proposed activating enzymes include histone deacetylases (HDACs) and the protease cathepsin L (CTSL), which are abundant in cancer cells. To activate the drug, the HDACs first deacetylate the lysine residue. Only after the deacetylation can CTSL remove the lysine from the puromycin, freeing it to kill any nearby cells by interrupting protein synthesis. The paper “introduces a clever way of ensuring the anticancer drug activates only in designated tumors by targeting two distinctive enzymes overexpressed in cancer cells,” Seulki Lee, who studies molecular imaging and drug delivery at the Johns Hopkins School of Medicine's Center for Nanomedicine and Department of Radiology and was not involved in the study, wrote in an email to The Scientist.
What’s new: Numerous tumor-targeting prodrugs are in development. But Boc-KAc-Puro is novel because it uses HDACs as triggering enzymes, and unleashing its toxicity involves two steps rather than one. “If you only have HDAC it won’t activate the drug,” said coauthor Nobuhide Ueki, a cancer biologist at Stony Brook University on Long Island, New York. “You need both HDAC and cathepsin L.” The two-step triggering process makes it less likely that a noncancer cell could unleash the drug’s toxicity. “Since the prodrug activates and demonstrates toxicity only after meeting the two unique enzymes in cancer cells, the system demonstrates increased specificity and safety compared to conventional prodrugs targeting a single enzyme,” said Lee. The researchers found that Boc-KAc-Puro was able to kill a variety of ...
