Modular PROTAC/IMiD Bifunctional Molecule Design for the Degradation of Synergistic Targets in the Treatment of Lymphoma

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-10-14 DOI:10.1021/acs.jmedchem.5c01159

Yuheng Jin, Xueyan 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

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引用次数: 0

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.

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模块化PROTAC/IMiD双功能分子设计降解淋巴瘤治疗中的协同靶点

利用imids诱导的新底物降解与PROTACs靶向蛋白破坏能力的协同效应，为对抗恶性肿瘤提供了一种有效的治疗策略。然而，确定协同靶点和相应的PROTAC/IMiD仍然是一个重大挑战。在这项研究中，我们提出了一种集成双功能分子设计导向（BMDO） IMiD库的综合方法。以BCL6为起始靶点，利用BCL6与IKZF1/3的正相关，开发出首个BCL6- protac /IMiD BC6。BC6对BCL6和IKZF1/3具有较高的选择性降解活性，对各种生发中心b细胞样（GCB）和活化b细胞样（ABC）弥漫性大b细胞淋巴瘤（DLBCL）细胞系均有较好的抗增殖作用，体内抗肿瘤效果显著。该过程还有助于发现新的BTK-PROTAC/IMiD BT6。这些结果为DLBCL的新治疗途径铺平了道路，对PROTAC/IMiD的设计具有广泛的意义。

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.