Researchers at MD Anderson have discovered a potentially new therapeutic approach for certain brain cancers in which the enzyme enolase (ENO1) has been deleted.The discovery was a surprise to the team who were investigating a potent enolase inhibitor called PhAH as a way to inhibit the enolase enzyme ENO2. Gliomas that have an EMO1 deletion are highly dependent on ENO2.
"We were working on generating a clinical candidate enolase inhibitor for the treatment of ENO1-passenger deleted tumors," said Florian Muller, assistant professor of Cancer Systems Imaging. "We undertook modeling and structure-aided design to synthesize drug-like derivatives of PhAH. Unexpectedly, a structure-based search revealed that PhAH bears strong similarity to SF2312, a phosphonate antibiotic of unknown mode of action produced by the bacteria micromonospora."
Micromonospora is commonly found in soil or water and has proved lethal to other common bacteria such as salmonella and staphylococcus. It is commonly used in antibiotic development.
Muller's team showed both in vitro and in cell-based systems, that SF2312 is an enolase inhibitor, making it perhaps the most potent natural product glycolysis enzyme inhibitor reported to date.
The researchers had previously demonstrated that ENO1-deleted glioma cells are more sensitive to PhAH than those in which ENO1 remained intact. SF2312 showed strong selective toxicity toward ENO1-deleted glioma cells and inhibited cell proliferation.
"The reason why ENO1-deleted glioma cells were so sensitive to ENO2 inhibition was that the cells retain only 10 percent of normal enzymatic activity, such that even low levels of inhibitors are sufficient to stop remaining enzymatic activity below the toxicity threshold," said Muller. "Our study showed that SF2312 proved superior to PhAH for killing EMO1-deleted glioma cells, especially under anaerobic conditions."