

Project details
ENU Team Leader: GABRIELLA NICOLINI
Other ENU members involved: ALESSIO MALACRIDA
Coordinator: GABRIELLA NICOLINI
Other Participants: FRANCESCA RE (School of Medicine and Surgery, University of Milano-Bicocca), MIRKO RIVARA (Food and Drug Department, University of Parma), VALENTINA ZULIANI (Food and Drug Department, University of Parma)
Funded by: FONDAZIONE GIOVANNI CELEGHIN CONTRO I TUMORI CEREBRALI
Total Contribution: 100.000 €
Project Duration in months: 24
Start date: June 2022
End date: June 2024
Project presentation available here:
Abstract
Since 2005, temozolomide (TMZ) has been used as a standard first-line treatment for glioblastoma (GBM, grade IV glioma), and despite many studies and efforts no better alternatives have emerged. Tumor recurrences and TMZ resistance are common and the prognosis is very poor with a median overall survival of 14–16 months. The development of new pharmacological strategies is even more difficult due to the presence of glioma stem cells (GSCs). Using a multidisciplinary strategy and starting from an innovative in silico analysis, in previous papers we have demonstrated the efficacy of the newly synthesized molecule imidazobenzoxazin-5-thione (MV1035). We have deeply investigated the in vitro effect of MV1035 on glioblastoma, using GBM 87-MG and 2 patient derived (PD) GSC lines. In particular we have demonstrated its capability to inhibit both ALKBH5 and ALKBH2 (both proteins involved in GBM malignancy) and its useful combination with TMZ as an effective approach to hinder glioma stem cell proliferation. Interestingly, MV1035 induces a reduction in MGMT expression in PD-GSC lines. These data make MV1035 a very promising and strong candidate to be further developed. The aim of our project is to pursue the optimisation of MV1035 by rationally designing a set of novel molecules with increased binding affinity towards ALKBH5 and ALKBH2 targets.
Through an in-depth analysis of the detailed information already in our hands, such as the position of the binding sites, the relative orientation of the molecule within the binding sites, the list of the most stabilizing amino acid residues to the ligand binding, and using molecular modelling techniques we will rationally design new compounds that will first be checked for their chemical feasibility, then synthesized and purified to obtain a suitable amount that will be used for biological validations. Together with potency the design will take into account also the ability of the newly designed compounds to cross, theoretically, the Blood Brain Barrier (BBB). After the initial screening to assess the potency of the newly synthesized compounds, the best candidates will be validated in a BBB in vitro model and the most promising molecules in terms of BBB permeability will be tested for their anti glioblastoma effect alone and in combination with TMZ in in vitro models.