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
  • 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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