Intervention in RNA switches off "cancer genes" / American-German team publishes study in "Nature"If the regulation of cell growth and division gets out of control, cancer is a possible consequence. The gene "MYC", for example, plays an important role in controlling cell growth in humans. If it no longer functions properly, cells grow uncontrollably. This is why this growth-promoting gene is also called the "cancer gene". An American-German research team has now described in the scientific journal "Nature" a new approach to switch off the MYC gene by specifically modifying the RNA. Among the scientists is Prof. Frank Glorius from the Organic Chemistry Institute of the WWU Münster.
The scientists' approach directs decomposing enzymes of the cells to the RNA of the "cancer genes" and cuts off key segments. This inactivates the genes and prevents them from causing damage. The effect comes from the researchers combining enzymes found in the cell with another molecular element. This compound, called RIBOTAC, worked against MYC and also against two other "cancer genes", JUN and MIR155. All three regulate the transcription of other genes. Attempts to develop drugs that prevent these three oncogenes from doing harm have largely failed so far due to their complex structural challenges.
"The lipid-like molecules we developed in Münster for membrane research are structurally based on an imidazolium ring system. In the screen, they proved to be unexpectedly selective binders for the micro RNA of the gene MIR155", underlines Frank Glorius. "Previously, it was completely unknown that azolium compounds could bind to RNA." This observation provided the basis for the production of RIBOTACs, which can bind and selectively degrade the RNA of some 'cancer genes'. "Unfortunately, we have not yet understood the exact nature of the binding between azolium and microRNA. A breakthrough in this area could enable targeted design - but more research needs to be done here."
For the researchers, the method is a promising approach for a possible new cancer therapy. Prof. Herbert Waldmann, Director of the Max Planck Institute of Molecular Physiology in Dortmund, says: "For cancer patients whose disease is driven by these common but challenging oncogenes, the RNA degrader approach could offer new hope. At this stage, however, the researchers emphasise, this is basic research and not a ready-made treatment method.
The study also opens up new possibilities for targeting drugs against RNA, so other genetic diseases may be candidates for this treatment approach, says chemist and Institute Professor Matthew D. Disney, Ph.D., of the Herbert Wertheim oeuf Scripps Institute for Biomedical Innovation & Technology and the oeuf Health Cancer Center, USA. "We discovered about 2,000 new RNA structures that can bind drug-like small molecules and identified six new chemotypes that can bind RNA," said Disney, who led the study.
By way of background, Herbert Waldmann's group designs compounds inspired by natural substances. Many antibiotics and cancer drugs have already emerged from such substances. Frank Glorius has developed innovative methods for building new bioactive molecules. Some of his compounds have been specifically designed to influence biology in cell membranes. Compounds derived from imidazole modified with carbon chains eventually proved most effective in binding to cancer-associated RNAs. Imidazole is a molecule commonly found in natural products and medicines.
For the study, tests were carried out on cancer cell cultures as well as on mice to assess lung colonisation by breast cancer cells.
Tong, Y., Lee, Y., Liu, X. et al. Programming inactive RNA-binding small molecules into bioactive degraders. Nature (2023). DOI: 10.1038/s41586’023 -06091-8