Synthesis of small molecules interfering with oncogenic microRNAs for the induction of glioblastoma stem cell differentiation

As main biological actors implicated in the regulation of many cellular processes, RNAs represent a particularly interesting target for the development of new therapeutic approaches. Many RNAs have a therapeutic interest, such as ribosomal RNAs, viral RNAs, nucleotide repeat expansion or microRNAs. These latter are a class of non-coding RNAs which is implicated in the regulation of gene expression by base pairing with messenger RNA and whose dysregulation is related to several diseases such as cancers. Indeed, in cancer cells some oncogenic microRNAs are overexpressed, this tends to promote oncogenesis and the maintenance of tumors. Also, oncogenic microRNAs are implicated in the maintenance of cancer stem cells (CSC). These tumorigenic cancer cells are resistant to current therapies and are the principal cause of therapeutic failure of chemotherapies. This failure is particularly important in the treatment of glioblastomas, an incurable brain cancer with a lifetime expectancy limited to 18 months, even with the combination of surgery, radiotherapy and chemotherapy. The main goal of my PhD work was to design, synthesize and characterize new small molecules, able to interfere with a step of oncogenic microRNAs' biogenesis in order to inhibit their production. This can also induce the differentiation of glioblastoma cancer stem cells and lead to a potential therapy for this incurable disease. Through the biochemical study of interaction between these molecules and the target, as well as cellular tests, we were able to identify structure activity relationships and identify molecules inducing CSC differentiation, in order to render them sensitive to classical chemotherapies.