A Comprehensive Monograph on 6-O-benzylguanine (DB11919): From Promising Chemosensitizer to Indispensable Research Tool

Executive Summary

6-O-benzylguanine, also known as O6-BG, is a synthetic small molecule analogue of guanine, rationally designed as a potent, mechanism-based inactivator of the DNA repair protein O⁶-alkylguanine-DNA alkyltransferase (MGMT).[1] Its development was predicated on a clear and compelling therapeutic rationale: to function as a chemosensitizing agent, thereby overcoming a primary mechanism of tumor resistance to a cornerstone class of anticancer drugs, the O⁶-alkylating agents. These agents, which include temozolomide (TMZ) and carmustine (BCNU), are critical in the treatment of various malignancies, particularly glioblastoma. Tumor resistance to these drugs is frequently mediated by high cellular levels of MGMT, which efficiently repairs the cytotoxic DNA lesions they induce.[3]

The molecular mechanism of 6-O-benzylguanine is one of elegant and potent "suicide" inhibition. It acts as a pseudosubstrate for MGMT, binding to the enzyme's active site and irreversibly transferring its benzyl group to a critical cysteine residue. This covalent modification permanently inactivates the MGMT protein, which is subsequently targeted for degradation, thereby preventing the repair of drug-induced DNA damage in cancer cells.[5] This blockade allows the cytotoxic lesions to persist, leading to futile DNA repair cycles, the formation of lethal double-strand breaks, and ultimately, apoptotic cell death.