2. Academic Validation
  3. Discovery of 2,4-quinazolinedione derivatives as LC3B recruiters in the facilitation of protein complex degradations

Discovery of 2,4-quinazolinedione derivatives as LC3B recruiters in the facilitation of protein complex degradations

  • Eur J Med Chem. 2025 Jan 19:287:117293. doi: 10.1016/j.ejmech.2025.117293.
Yanping Zeng 1,  Jian Xiao 2,  Li Shi 3,  Yangsha Li 2,  Yuanxin Xu 4,  Jiayun Zhou 5,  Xiao Dong 2,  Haiyang Hou 2,  Chao Zhong 5,  Gang Cheng 6,  Yi Chen 7,  Naixia Zhang 8,  Yanfen Fang 9,  Youhong Hu 10
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, 1 Xiangshanzhi Road, Hangzhou, 310024, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China.
  • 3 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
  • 4 Nanjing University of Chinese Medicine, School of Chinese Materia Medica, 138 Xianlin Road, Nanjing, 210046, China.
  • 5 School of Life Sciences, Fudan University (Jiangwan Campus), 2005 Songhu Road, Yangpu District, Shanghai, 200433, China.
  • 6 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China.
  • 7 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China.
  • 8 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China. Electronic address: nxzhang@simm.ac.cn.
  • 9 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China. Electronic address: yffang@simm.ac.cn.
  • 10 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, 1 Xiangshanzhi Road, Hangzhou, 310024, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China. Electronic address: yhhu@simm.ac.cn.
PMID: 39923533 DOI: 10.1016/j.ejmech.2025.117293
Abstract

Targeted protein degradation through autophagosome-tethering compounds (ATTECs) that bypasses the ubiquitination process has garnered increasing attention. LC3B, a key protein in autophagosome formation, recruits substrates into the autophagy-lysosome system for degradation. In this study, we systematically optimized 2,4-quinazolinedione derivatives as LC3B-recruiting fragments, utilizing the CDK9 indicator. By attaching the designed LC3B-recruiting fragment to CDK9 Inhibitor SNS-032 through a linker, the resulting bifunctional ATTEC molecule simultaneously degraded CDK9 and its associated Cyclin T1. Two-dimensional NMR experiments confirmed the direct interaction between the novel LC3B-recruiting fragments and LC3B. Mechanistic studies elucidated that degradation occurred via an LC3B-dependent autophagy-lysosomal pathway. Additionally, the general applicability of leveraging LC3B-recruiting fragments linked to inhibitors for the targeted degradation of protein complexes was validated with PRC2 and CDK2/4/6 along with their respective Cyclins. This work provides a series of novel LC3B-recruiting fragments that enrich the ATTEC toolbox and can be applied to the degradation of diverse intracellular disease-causing proteins.

Keywords

CDK9; Degradation; LC3B; Protein complex.

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