Novel non-nucleoside MGMT inhibitors: potential in combined alkylating chemotherapy

Abstract

Aim. O⁶-methylguanine-DNA methyltransferase (MGMT) is an inducible repair enzyme that removes alkyl residues from DNA, thereby reducing the effectiveness of alkylating chemotherapy. Therefore, the MGMT inhibitors are used in medical practice. However, the most common of them, O⁶-benzylguanine and its analogs, have proven to be toxic to hematopoietic cells. That is why the search for new alternative inhibitors is essential. Conclusions. The new low molecular weight non-nucleoside MGMT inhibitors effectively reduce MGMT protein levels and enhance the cytotoxic effects of MNNG across different cancer cell lines. In T98G cells, the combination treatment increases autophagy and makes cells more sensitive to MNNG. The in vivo study confirms the therapeutic potential of these inhibitors, with significant tumor reduction or remission observed. Inhibitor 41B demonstrated the greatest overall efficacy, making it a promising candidate for further development in the combined alkylating chemotherapy.