Modular PROTAC/IMiD Bifunctional Molecule Design for the Degradation of Synergistic Targets in the Treatment of Lymphoma
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 <b>BC6</b> was developed by leveraging the positive correlation between BCL6 and IKZF1/3. <b>BC6</b> 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 <b>BT6</b>. These results pave the way for a promising new treatment avenue for DLBCL, with broad implications for the design of PROTAC/IMiD.
Authors
- Xiaowu Dong (ORCID: https://orcid.org/0000-0002-2178-4372)
- Jia Wang (ORCID: https://orcid.org/0000-0002-3110-3892)
- Guoxin Cai (ORCID: https://orcid.org/0000-0001-7645-0436)
- Shenxin Zeng (ORCID: https://orcid.org/0000-0003-3326-8380)
- Wenhai Huang (ORCID: https://orcid.org/0000-0003-1457-7380)
- Xiang Liao (ORCID: https://orcid.org/0000-0002-2485-6167)
- Yuheng Jin (ORCID: https://orcid.org/0009-0001-0516-3293)
- Zhan Zhou (ORCID: https://orcid.org/0000-0002-2730-5483)
- Yubo Zhou (ORCID: https://orcid.org/0000-0002-0694-3697)
- Jinxin Che (ORCID: https://orcid.org/0000-0001-7202-9214)
- Cong Li (ORCID: https://orcid.org/0000-0003-0312-0107)
- Lei Xu (ORCID: https://orcid.org/0000-0003-0010-9738)
- Jingyu Zhang (ORCID: https://orcid.org/0000-0003-4820-577X)
- Jia Li (ORCID: https://orcid.org/0000-0003-1500-869X)
- Linjie Li (ORCID: https://orcid.org/0000-0002-9386-112X)
- Xian Li (ORCID: https://orcid.org/0009-0002-8129-3812)
- Haiting Duan
- Xiaoli Yu
- Ran Xu (ORCID: https://orcid.org/0000-0001-5023-3281)
- Yang Lu (ORCID: https://orcid.org/0000-0002-0383-2289)
- Xiaomin Luo (ORCID: https://orcid.org/0000-0003-0426-3417)
- Bizhi Li (ORCID: https://orcid.org/0000-0002-7774-5452)
Institutions
- Nanjing University of Chinese Medicine (CN)
- Zunyi Medical University (CN)
- Chinese Academy of Sciences (CN)
- Sichuan Agricultural University (CN)
- Neuropsychiatric Research Institute (US)
- Shanghai Institute of Materia Medica (CN)
- Drug Discovery Laboratory (Norway) (NO)
- Kindeva Drug Delivery (United States) (US)
- University of Chinese Academy of Sciences (CN)
- Hangzhou Medical College (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-10-14
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01159
- Citations
- 2
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 1.61