Pharmacological Study of Novel Small-Molecule Inhibitors Targeting B-Cell Lymphoma 9/β-Catenin in the Treatment of Glioma

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Glioblastoma (GBM), one of the most aggressive and lethal primary brain tumors, remains a major challenge in neuro-oncology. The Wingless/Int-1 (Wnt)/β-catenin pathway has emerged as a potential therapeutic target for gliomas. However, owing to the lack of small-molecule inhibitors targeting B-cell lymphoma 9 (BCL9), a coactivator of β-catenin, the therapeutic potential of BCL9 in GBM has not been pharmacologically validated. Here, we report a novel small-molecule inhibitor of the BCL9/β-catenin interaction, designated ZD37-28R. Molecular docking suggested that ZD37-28R binds to β-catenin with high affinity. In vitro, ZD37-28R disrupted the interaction between BCL9 and β-catenin, markedly inhibited β-catenin-dependent transcriptional activity, and reduced the proliferation and migration of U87-MG and U251 GBM cells. Oil Red O staining and fluorescence-activated cell sorting further showed that ZD37-28R decreased lipid accumulation and lipid reactive oxygen species in GBM cells. These effects were associated with reduced expression of sterol regulatory element-binding protein 1 (SREBP1), a key regulator of lipid metabolism, thereby further impairing the viability and migration of glioma cells. In a subcutaneous glioma model, ZD37-28R exhibited robust antitumor activity with low toxicity. In an orthotopic glioma model, ZD37-28R showed antitumor efficacy and enhanced the effect of temozolomide (TMZ), as evaluated by magnetic resonance imaging. Taken together, our study identifies ZD37-28R as a novel BCL9/β-catenin inhibitor and suggests that it may represent a promising lead compound for GBM treatment, particularly in combination with TMZ.