Novel imidazotetrazine derivatives overcome temozolomide resistance in glioblastoma by inducing ferroptosis and apoptosis.

Glioblastomas (GBM) is a highly malignant primary brain tumor with poor prognosis despite standard treatments of surgery, radiotherapy, and chemotherapy. Temozolomide (TMZ) is a key chemotherapeutic agent for GBM but is limited by resistance mechanisms. In this study, we developed a novel imidazotetrazine analogs to overcome TMZ resistance with enhanced therapeutic efficacy. CCK8 assays demonstrated that QX302 showed remarkable potency and effectively inhibited the viability of U251, U87, T98G, and HCT116 cells in a dose- and time-dependent manner. Proteomic analysis indicated that QX302 affected critical pathways, including nucleotide binding, chromatin organization, cell cycle regulation, and DNA repair processes. Further investigations revealed that QX302 effectively inhibits glioma spheroid growth and induces cell cycle arrest, ferroptosis, and apoptosis. Notably, QX302 induced DNA damage in cancer cells via the alkylation of DNA, leading to increased sensitivity to Olaparib via the base excision repair signaling pathway. Predictive modeling demonstrated QX302 has a favorable pharmacokinetic profile, including high blood-brain barrier permeability, highlighting its potential as a central nervous system-penetrating therapeutic agent. In conclusion, QX302 represents a promising therapeutic strategy for GBM, offering improved efficacy and the potential for use in combinatorial therapy with lower effective doses compared to TMZ.