Discovery of a Selective and Potent BCL6 PROTAC with Efficacious Antiproliferative Activity for the Treatment of Diffuse Large B-Cell Lymphoma.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-09-30 DOI:10.1021/acs.jmedchem.5c01237

Xiaoli Yu,Xueyan Liao,Jingyu Zhang,Hanlin Wang,Xian Li,Jialiang Lu,Huan Zhou,Mingfei Wu,Yuheng Jin,Xin Zhu,Lei Xu,Shenxin Zeng,Youlu Pan,Jia Li,Jinxin Che,Yubo Zhou,Xiaowu Dong

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引用次数: 0

Abstract

B-cell lymphoma 6 (BCL6) is a key transcriptional repressor implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL). However, current BCL6-targeting agents demonstrate restricted efficacy in vitro and in vivo, and the underlying mechanism remains unclear. In this study, we identified A19 as a potent BCL6 PROTAC through comprehensive structure-activity relationship (SAR) analysis. A19 induces rapid and efficient BCL6 degradation (DC50 = 34 pM in OCI-LY1 cells) and displays superior antiproliferative activity compared to the molecular glue BI3802 across multiple DLBCL cell lines. In addition, RNA-seq profiling showed that A19 and BI3802 trigger comparable changes in signaling pathways, reflecting similar transcriptomic responses. Further, oral dosing of A19 led to BCL6 degradation and inhibition of tumor growth in vivo. Overall, A19 is a valuable chemical tool and a promising lead compound toward the development of BCL6-dependent DLBCL.

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发现一种具有有效抗增殖活性的选择性强效BCL6 PROTAC治疗弥漫性大b细胞淋巴瘤。

b细胞淋巴瘤6 （BCL6）是弥漫性大b细胞淋巴瘤（DLBCL）发病机制中的关键转录抑制因子。然而，目前的bcl6靶向药物在体内外的疗效有限，其潜在机制尚不清楚。在这项研究中，我们通过综合构效关系（SAR）分析确定了A19是一个有效的BCL6 PROTAC。A19诱导BCL6快速有效降解（OCI-LY1细胞中DC50 = 34 pM），并在多种DLBCL细胞系中表现出比分子胶BI3802更强的抗增殖活性。此外，RNA-seq分析显示，A19和BI3802在信号通路上触发了相似的变化，反映了相似的转录组反应。此外，口服A19可导致体内BCL6降解并抑制肿瘤生长。综上所述，A19是一种有价值的化学工具，也是开发bcl6依赖性DLBCL的有前景的先导化合物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.