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

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

  • J Med Chem. 2025 Oct 9;68(19):20180-20206. doi: 10.1021/acs.jmedchem.5c01237.
Xiaoli Yu 1,  Xueyan Liao 2 3,  Jingyu Zhang 1,  Hanlin Wang 4 5,  Xian Li 2,  Jialiang Lu 1,  Huan Zhou 1,  Mingfei Wu 1,  Yuheng Jin 1,  Xin Zhu 1 6,  Lei Xu 7,  Shenxin Zeng 8,  Youlu Pan 8,  Jia Li 2 3 4 5,  Jinxin Che 1,  Yubo Zhou 2 5,  Xiaowu Dong 1
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong 528400, China.
  • 3 School of Pharmacy, Zunyi Medical University, Zunyi 563006, China.
  • 4 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 6 College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China.
  • 7 Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 213001, China.
  • 8 Hangzhou Medical College, Hangzhou, Zhejiang 310053, China.
PMID: 41025654 DOI: 10.1021/acs.jmedchem.5c01237
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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