New Investigator Grant Awarded to Jean Borges Bertoldo

Diffuse midline glioma/diffuse intrinsic pontine glioma (DMG/DIPG) is an aggressive type of brain tumor that primarily affects children. The burden of DIPG lies in its high mortality rate and limited treatment options, often leading to a poor prognosis. One significant finding in DIPG research is the discovery of histone H3K27M mutation which occurs in both histone H3.1 and H3.3 isoforms, that combined affect more than 80% of DIPG patients1. This mutation plays a crucial role in the development and progression of the disease, which leads to changes in the epigenetic regulation of genes, contributing to tumor formation. Targeting this specific mutation could open doors to more effective and less toxic therapies, offering hope for patients and their families grappling with this devastating disease. The challenge lies in developing inhibitors for H3K27M, which is currently considered "undruggable". This means that traditional drug development methods, which typically target proteins with well-defined pockets or binding sites, face significant hurdles when it comes to this mutation. The lack of easily targetable sites on the mutant histone protein makes it difficult to design drugs that can effectively inhibit its function. In this grant we will use our expertise in protein chemistry and covalent drug discovery to overcome these hurdles by going beyond “traditional methods” and developing an innovative platform to drug the “undruggable” H3K27M. We will employ chemoproteomics – a method that combines chemistry and proteomics to decode interactions between chemical probes and proteins, and AI-driven drug discovery – a method that uses chemoproteomics data and machine learning to accelerate the development of novel H3K27M-targeting drugs. Our preliminary findings with a cysteine-directed covalent probe named JNSY1 demonstrate the feasibility of our platform. We have found that JNSY1 selectively binds to H3.1K27M in DIPG cells, restores epigenetic changes caused by H3.1K27M, and induces selective cytotoxicity to DIPG cells when compared to normal fibroblasts, which revealed an interesting isoform specific mechanism of action. Our overall goal is to further optimize JNSY1, discover and optimize covalent probes targeting H3.3K27M, and evaluate the potential of these small molecules as novel DIPG targeted drugs. This will allow the development of the first-in-class inhibitor/modulator that specifically tackles the most prevalent underlying cause of DIPG.