Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
Eur J Med Chem. 2024 Nov 5;277:116789. doi: 10.1016/j.ejmech.2024.116789. Epub 2024 Aug 23.
The transcriptional repressor B cell lymphoma 6 (BCL6) plays a critical role in driving tumorigenesis of diffuse large B-cell lymphoma (DLBCL). However, the therapeutic potential of inhibiting or degrading BCL6 for DLBCL has not been thoroughly understood. Herein, we reported the discovery of a series of novel BCL6-targeting PROTACs based on our previously reported N-phenyl-4-pyrimidinamine BCL6 inhibitors. The optimal compound DZ-837 degraded BCL6 with DC values around 600 nM and effectively inhibited the proliferation of several DLBCL cell lines. Further study indicated that DZ-837 induced significant G1 phase arrest and exhibited sustained reactivation of BCL6 downstream genes. In the SU-DHL-4 xenograft model, DZ-837 significantly inhibited tumor growth with TGI of 71.8 % at 40 mg/kg once daily. Furthermore, the combination of DZ-837 with BTK inhibitor Ibrutinib showed synergistic effects and overcame acquired resistance against DLBCL cells. Overall, our findings demonstrate that DZ-837 is an effective BCL6 degrader for DLBCL treatment as a monotherapy or in combination with Ibrutinib.
转录抑制剂 B 细胞淋巴瘤 6（BCL6）在驱动弥漫性大 B 细胞淋巴瘤（DLBCL）的肿瘤发生中起着关键作用。然而，抑制或降解 BCL6 治疗 DLBCL 的治疗潜力尚未得到充分理解。在此，我们报告了一系列基于我们之前报道的 N-苯基-4-嘧啶胺 BCL6 抑制剂的新型 BCL6 靶向 PROTAC 的发现。最佳化合物 DZ-837 以约 600 nM 的 DC 值降解 BCL6，并有效抑制几种 DLBCL 细胞系的增殖。进一步的研究表明，DZ-837 诱导明显的 G1 期停滞，并表现出 BCL6 下游基因的持续再激活。在 SU-DHL-4 异种移植模型中，DZ-837 以 40mg/kg 每天一次的剂量显著抑制肿瘤生长，TGI 为 71.8%。此外，DZ-837 与 BTK 抑制剂伊布替尼联合使用显示出协同作用，并克服了对 DLBCL 细胞的获得性耐药。总体而言，我们的研究结果表明，DZ-837 是一种有效的 BCL6 降解剂，可作为单药或与伊布替尼联合用于治疗 DLBCL。
