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 -phenyl-4-pyrimidinamine BCL6 inhibitors. The optimal compound degraded BCL6 with DC values around 600 nM and effectively inhibited the proliferation of several DLBCL cell lines. Further study indicated that induced significant G1 phase arrest and exhibited sustained reactivation of BCL6 downstream genes. In the SU-DHL-4 xenograft model, significantly inhibited tumor growth with TGI of 71.8 % at 40 mg/kg once daily. Furthermore, the combination of with BTK inhibitor Ibrutinib showed synergistic effects and overcame acquired resistance against DLBCL cells. Overall, our findings demonstrate that is an effective BCL6 degrader for DLBCL treatment as a monotherapy or in combination with Ibrutinib.

中文翻译：

---

发现新型 BCL6 靶向 PROTAC，在体外和体内对 DLBCL 具有有效的抗肿瘤活性


转录抑制因子 B 细胞淋巴瘤 6 (BCL6) 在驱动弥漫性大 B 细胞淋巴瘤 (DLBCL) 的肿瘤发生中发挥着关键作用。然而，抑制或降解 BCL6 对 DLBCL 的治疗潜力尚未得到充分了解。在此，我们报告了基于我们之前报道的-苯基-4-嘧啶胺 BCL6 抑制剂发现了一系列新型 BCL6 靶向 PROTAC。最佳化合物以约 600 nM 的 DC 值降解 BCL6，并有效抑制多种 DLBCL 细胞系的增殖。进一步的研究表明，诱导显着的 G1 期停滞并表现出 BCL6 下游基因的持续重新激活。在 SU-DHL-4 异种移植模型中，每天一次 40 mg/kg 时，可显着抑制肿瘤生长，TGI 为 71.8%。此外，与BTK抑制剂伊布替尼联合显示出协同效应，克服了DLBCL细胞的获得性耐药。总体而言，我们的研究结果表明，作为单一疗法或与依鲁替尼联合治疗，它是 DLBCL 治疗的有效 BCL6 降解剂。