Modular PROTAC/IMiDBifunctional Molecule Design forthe Degradation of Synergistic Targets in the Treatment of Lymphoma

作者：Yuheng Jin, Xiang Liao, Jingyu Zhang, Haiting Duan, Ran Xu, Xiaomin Luo, Xiaoli Yu, Bizhi Li, Jia Wang, Xian Li, Cong Li, Lei Xu, Linjie Li, Yang Lu, Guoxin Cai, Zhan Zhou, Shenxin Zeng, Wenhai Huang, Jia Li, Yubo Zhou, Xiaowu Dong, Jinxin Che · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c01159 · 被引用次数：4 · 研究领域：Protein Degradation and Inhibitors、CAR-T cell therapy research、Ubiquitin and proteasome pathways

Abstract Leveraging the synergistic effects of IMiDs-induced neo-substrate degradation with the targeted protein destruction capability of PROTACs offers a potent therapeutic strategy for combating malignancies. However, identifying synergistic targets and the corresponding PROTAC/IMiD is still a significant challenge. In this study, we present a comprehensive approach that integrates a bifunctional molecule design-oriented (BMDO) IMiD library. Taking BCL6 as a starting target, the first BCL6-PROTAC/IMiD BC6 was developed by leveraging the positive correlation between BCL6 and IKZF1/3. BC6 exhibits high selective degradation activity of BCL6 and IKZF1/3, demonstrating superior antiproliferative effects in various germinal center B-cell-like (GCB) and activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) cell lines and significant in vivo antitumor efficacy. The process also facilitates the discovery of a novel BTK-PROTAC/IMiD BT6. These results pave the way for a promising new treatment avenue for DLBCL, with broad implications for the design of PROTAC/IMiD.