One of the main problems in using immune checkpoint inhibitors (e.g. PD-L1/PD-1/PD-L2/CTLA4) as a cancer treatment is that there is a large percentage of patients (~60-70%) who do not respond to the treatment or become resistant to it. Researchers all over the world are looking for ways to increase response to immunotherapy in this large population of patients, such as identifying new signaling pathways and/or new targets involved in this process as well as identifying synthetic molecules that can modulate the functions of those pathways and targets.
that bind to relevant targets related to the N6-methylation of adenosine (m6A) in RNA which affect immunotherapy response in cancer patients. Different inhibitors identified by the researchers bind to different targets specifically. For example, a first group of compounds binds specifically to certain methyltransferases, which install m6A on RNA (e.g. METTL3/14). A second group binds to specific demethylases which remove methyl groups from m6A. A third group of compounds binds to a demethylase involved in alkylated DNA repair. Then a fourth group binds to a certain family of proteins that promote translation via interaction with translation initiation factors or promote RNA degradation via recruitment of m6A modified mRNA to nuclear processing bodies. Finally, a fifth group of inhibitors bind to a phosphatase in tumor cells and increase the efficacy of immunotherapy by enhancing IFN-g mediated effects on antigen presentation and tumor growth suppression. The inventors have predicted the compounds will have a good pharmacokinetics profile based on in vitro parameters of selected compounds.
The identified inhibitors will be useful to treat patients with glioblastoma, colon, lung, pancreatic, gastric, resistant breast cancer, and esophageal cancers by sensitizing those tumors to immune checkpoint inhibitors.