New ALKBH2 and ALKBH5 inhibitors for treating glioblastoma

Abstract

Purpose: Glioblastoma is an aggressive brain tumor with high mortality and a median survival of about 15 months. Starting from our previous published compound, MV1035 that inhibited migration and invasiveness of glioblastoma U87 cells, and also exhibited a synergic effect in combination with the alkylating agent Temozolomide, we identified new active molecules, with the aim to understand the key motifs responsible for MV1035 activity against the DNA repair protein ALKBH2 and the RNA demethylase ALKBH5. Materials and methods: We modified the original structure of MV1035, synthesizing new molecules that have been tested through MTT assay, cell-free ALKBH2 assay and cell-free ALKBH5 assay. Results: We found that compound 6 is able to reduce the activity of both ALKBH2 and ALKBH5. Conclusion: We obtained important information about the key motifs responsible for the activity of these inhibitors. However, considering the complexity, heterogeneity and plasticity of GBM and GSC cells, the new identified compound will need to be validated in vivo.

Keywords

• Brain cancer
• Glioblastoma
• ALKBH2 inhibitors
• ALKBH5 inhibitors