Current landscape of small molecule MGMT expression inhibitors as potential resistance reversers for glioblastoma

Primary or acquired temozolomide (TMZ) resistance in glioblastoma (GBM) critically limits clinical efficacy, with O6‑methylguanine‑DNA methyltransferase (MGMT) serving as the key repair protein that directly reverses TMZ-induced O6-methylguanine (O6-MG) lesions. Classical MGMT inactivators such as O6‑benzylguanine (O6‑BG) and O6‑(4‑bromothenyl)guanine (O6‑4‑BTG, lomeguatrib) effectively deplete MGMT activity and sensitize tumor cells to alkylating agents. However, their lack of tumor selectivity depletes MGMT in normal hematopoietic tissues, inducing dose-limiting myelotoxicity and necessitating counterstrategies such as MGMT-tolerant hematopoietic stem cell protection. To overcome this bottleneck, MGMT intervention strategies have expanded from direct enzymatic inhibition toward regulation at the expression level. This review focuses on small molecules that downregulate MGMT expression through transcriptional and epigenetic regulation, CNS-active drug interventions, modulation of MGMT-related signaling pathways, and naturally derived bioactive compounds. It also summarizes emerging technological approaches including tumor-targeted conjugation, blood–brain barrier-penetrating delivery systems, MGMT gene silencing via siRNA, and induced protein degradation through ubiquitin-proteasome modulation. The expression-regulation strategy offers a broader therapeutic window for restoring GBM sensitivity to TMZ. Nevertheless, clinical translation still requires further optimization in tumor selectivity, effective brain exposure, rational combination timing, and robust pharmacodynamic validation to establish meaningful patient benefit.