Current landscape of small molecule MGMT expression inhibitors as potential resistance reversers for glioblastoma
Year: 2026
Type: article
Abstract: 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. Glioblastoma (GBM) is an aggressive brain cancer with a poor outlook. The standard treatment includes the chemotherapy drug temozolomide (TMZ), but many tumors become resistant to it. This resistance is largely driven by a protein called MGMT, which acts like a “repair worker” inside cancer cells. When TMZ damages the cancer cell’s DNA, MGMT fixes the damage before the cell can be killed. The higher the MGMT levels, the less effective the chemotherapy. Researchers have developed drugs to block MGMT directly, but these drugs also remove MGMT from healthy bone marrow cells, causing serious side effects that limit their use. Therefore, scientists are now looking at ways to lower MGMT levels more selectively – by silencing the MGMT gene, disrupting the signals that turn it on, or breaking down the MGMT protein itself. Some existing drugs, including anti-seizure medications and antidepressants, have been found to reduce MGMT in tumor cells, offering a potential shortcut to new treatments. Other approaches use nanoparticles to deliver MGMT-blocking molecules specifically to brain tumors, or protect healthy bone marrow so stronger chemotherapy can be given. This review summarizes the latest strategies to overcome MGMT-related resistance, highlighting the shift from simply blocking MGMT to more sophisticated methods that aim to make GBM vulnerable to treatment again while sparing healthy tissues.
Source: Figshare
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7225760481
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