Dual Targeting of DNA and EGFR by ZYH005: A Novel Strategy to Induce DNA Damage and Inhibit EGFR-WEE1 Interaction in Glioblastoma Treatment
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Background
Glioblastoma (GBM) is a highly aggressive malignancy with limited therapeutic option. EGFR and WEE1 play specific roles in the occurrence and development of GBM and are potential therapeutic targets for it. ZYH005 (Z5) is a DNA intercalator with low systemic toxicity and enhanced blood-brain barrier penetration, its therapeutic efficacy and underlying mechanisms in GBM are worth further exploration.
Methods
The antitumor efficacy of Z5 was determined with GBM cell lines and patient-derived glioblastoma stem cells (GSCs) in vitro and in vivo through cell proliferation, colony formation and western blots assays. The targets of Z5 and related mechanisms were validated using CMap, DNA microarrays and surface plasmon resonance (SPR).
Results
Z5 demonstrated robust anti-proliferative activity against both conventional GBM cell lines and patient-derived glioblastoma stem cells (GSCs), while significantly suppressing orthotopic tumor growth and prolonging survival in murine models. Mechanistic studies revealed a dual mechanism of action: Z5 directly induces persistent DNA damage and inhibits DNA repair pathways, while simultaneously binding to EGFR’s Glu762 residue to disrupt its interaction with WEE1. This interference blocks WEE1 phosphorylation at Ser642, abrogating G2/M checkpoint activation and triggering mitotic catastrophe in cells.
Conclusions
These results clearly demonstrate the dual functionality of Z5, which serves as both a DNA intercalator and an EGFR inhibitor. In GBM cells, Z5 effectively induces mitotic catastrophe, and in GSCs-based models, it exhibits remarkable anti - tumor activity. Consequently, Z5 stands out as a highly promising candidate for the development of innovative GBM treatments.
