image: (A) Homogenous time-resolved fluorescence (HTRF) assay screening schematic. (B) HTRF assay screening compounds. (C) HTRF assay showed that the effect of FX1, BI-3802, and YK01 blocked the interaction between BCL6-BTB and SMRT. (D) Chemical structure of compound FX1, BI-3802, and YK01. (E) Schematic diagram of a luciferase reporter plasmid screening model. GAL4-DBD-BCL6-BTB bound to (GAL4)5-TK-LUC to inhibit fluorescence expression, and the fluorescence value recovered after the substance. (F) FX1, BI-3802, and YK01 inhibited BCL6-BTB-mediated transcriptional repression in luciferase reporter assays. (G) Reporter assays were performed to test the activities of YK01 with different BTB-related proteins (BCL6, Kaiso, and PLZF). (H) SPR sensorgram of YK01 binding to BCL6BTB, with YK01 concentrations and calculated KD for binding shown. (I) C57/BL6 mice were immunized with NP18-CGG and intraperitoneally administered YK01 at a dosage of 50 mg/kg/d for 12 days to further detect whether YK01 could inhibit the transcriptional inhibitory function of BCL6 in vivo. (J) Flow cytometry detection of splenic GC-B cells (B220+GL7+FAS+) percentage and statistical graph of the total number of B cells or the percentage of GC-B cells in the mouse spleen. **P < 0.01 and ****P < 0.0001.
Credit: Min Wu, Lin Zhang, Weikai Guo, Shiyi Lv, Wangrui Jin, Shuangshuang Zhu, Huang Chen, Shuyi Jian, Layang Liu, Yajing Xing, Shihong Peng, Mingyao Liu, Yihua Chen, Zhengfang Yi
Glioblastoma multiforme (GBM), the most aggressive tumor of the central nervous system, is highly malignant, resistant to existing drug therapies and associated with high mortality rates. Overexpression of B-cell lymphoma 6 (BCL6) has been frequently observed in GBM patients, highlighting the urgent need for potent BCL6 inhibitors as a novel treatment strategy.
This research, published in the Genes & Diseases journal by a team from East China Normal University, Kunming Medical University, and Shanghai Yuyao Biotech Co., LTD. identifies the key role of BCL6 in promoting the proliferation of glioma cells and the progression of glioma.
Initially, the team analysed the data from The Cancer Genome Atlas and Cancer Cell Line Encyclopedia and revealed that BCL6 is significantly overexpressed in GBM tumors and correlates strongly with poor patient prognosis. Experiments in GBM cell lines confirmed that silencing BCL6 reduced cell viability and proliferation, while overexpressing BCL6 had the opposite effect—indicating that the survival of GBM cells is highly dependent on BCL6.
To improve the biological activities of BCL6 inhibitors, researchers developed YK01, a novel small-molecule inhibitor that can directly bind to the BCL6-BTB domain and inhibit its biological functions in vitro and in vivo, thus confirming YK01 as a potential compound for the treatment of tumors with high expression of BCL6. Additionally, MTS experiments demonstrated YK01’s exceptional potency, with nanomolar binding affinity, effectively suppressing BCL6 activity in both cell-based assays and animal models.
Notably, YK01 not only blocked the interaction between BCL6 and its corepressors (SMRT) but also induced degradation of BCL6 protein, reactivating tumor suppressor genes and triggering DNA damage responses. Importantly, YK01 significantly reduced the growth and invasiveness of GBM cells in vitro and potently suppressed GBM growth in a mouse subcutaneous glioma transplantation model without toxicity. Furthermore, results revealed that YK01 and the chemotherapy drug temozolomide (TMZ) had synergistic anti-GBM effects, and the combination of YK01 effectively inhibited the in situ tumor growth of GBM and significantly prolonged survival.
In conclusion, this study highlights BCL6 as a promising therapeutic target in GBM and validates YK01 as a potential new treatment strategy. Given the lack of effective therapies for GBM, this dual approach—targeting BCL6 directly and enhancing the chemotherapy response—could offer real clinical impact.
Reference
Title of Original Paper: Selectively targeting BCL6 using a small-molecule inhibitor is a potential therapeutic strategy for glioblastoma
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch
DOI: https://doi.org/10.1016/j.gendis.2025.101644
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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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