Novel peptidomimetics for inhibition of MDM2 in glioblastoma

Objective

Mouse double minute 2 homolog (MDM2) is a primary antagonist of p53 tumour suppressor, and MDM2 inhibition represents an attractive way to restore p53 function. Peptidomimetics which are based on p53 sequence-derived structure, are one of the most promising tools for mimicking MDM2/p53 interaction. Varying structure of peptidomimetics gives opportunity to measure effect of fine structure changes on inhibition process. Linking peptidomimetics with fluorophores represents an attractive way to spatially track inhibition process. In this project we aim to synthesize novel fluorophore-peptidomimetic probes (FPPs) for MDM2 inhibition. Fluorophores triarylboranes will be covalently linked to peptidomimetics and introduced into patient-derived glioma stem cells. In the first part of the project we will detect effect of MDM2 inhibition on major histocompatibility (MHC-I) peptides presentation at cell surface. Further, we aim to investigate immunogenic response of CD4+ T cells on MHC-I peptides presentation. In the second part of the project we will investigate effect of proteasomal inhibition on MDM2 and p53 degradation, and their role in composition of MHC-I peptides. Immune response on presentation of novel MHC-I repertoire at the cell surface will be tested with co-cultivation with CD4+ T cells. By focusing on these particular pathways, GlioLight intends to hinder the processes that enable GBM cells to grow and escape standard treatments. Ultimately, this effort paves the way for advancements in personalized medicine.