2. Academic Validation
  3. Modular PROTAC/IMiD Bifunctional Molecule Design for the Degradation of Synergistic Targets in the Treatment of Lymphoma

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

  • J Med Chem. 2025 Oct 23;68(20):21249-21281. doi: 10.1021/acs.jmedchem.5c01159.
Yuheng Jin 1,  Xueyan Liao 2 3,  Jingyu Zhang 1,  Haiting Duan 1,  Ran Xu 4,  Xiaomin Luo 2,  Xiaoli Yu 1,  Bizhi Li 1,  Jia Wang 5,  Xian Li 2,  Cong Li 6,  Lei Xu 2,  Linjie Li 1,  Yang Lu 1,  Guoxin Cai 7,  Zhan Zhou 7,  Shenxin Zeng 8,  Wenhai Huang 8,  Jia Li 2 9 3 6,  Yubo Zhou 2 4 9,  Xiaowu Dong 1,  Jinxin Che 1
Affiliations

Affiliations

  • 1 Institute of Drug Discovery and Design, 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, Guangdong 528400, China.
  • 3 School of Pharmacy, Zunyi Medical University, Zunyi 563006, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 5 College of Science, Sichuan Agricultural University, Ya'an 625104, China.
  • 6 Stake Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 7 National Key Laboratory of Advanced Drug Delivery and Release Systems & Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 8 Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou 310013, China.
  • 9 University of Chinese Academy of Sciences, Beijing 100049, China.
PMID: 41086092 DOI: 10.1021/acs.jmedchem.5c01159
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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