Structure-Based Design and Discovery of a Potent and Cell-Active LC3A/B Covalent Inhibitor

  • J Med Chem. 2024 Jul 25;67(14):12184-12204. doi: 10.1021/acs.jmedchem.4c00898.
Zhenfei Zhou  1  2  3 ,  Siqi Huang  2  4 ,  Shijie Fan  3 ,  Xueyuan Li  3  5 ,  Chengyu Wang  3 ,  Wanlin Yu  3  5 ,  Daohai Du  2 ,  Yuanyuan Zhang  2  4 ,  Kaixian Chen  1  2  4 ,  Wei Fu  1 ,  Cheng Luo  2  4  3  6  7
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 2. Drug Discovery and Design Center and The Center for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong 528400, China.
  • 4. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China.
  • 6. State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China.
  • 7. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
PMID: 39010658 DOI: 10.1021/acs.jmedchem.4c00898
Abstract

Autophagy is a highly conserved cellular homeostasis maintenance mechanism in eukaryotes. Microtubule-associated protein light chain 3 (LC3) plays a crucial role in Autophagy. It has multiple pairs of protein-protein interactions (PPIs) with Other proteins, and these PPIs have an effect on the regulation of autophagosome formation and the recruitment of autophagic substrates. In our previous work, a small molecule covalent inhibitor DC-LC3in-D5 which could inhibit LC3A/B PPIs was identified, but a detailed study of structure-activity relationships (SARs) was lacking. Herein, a new molecule LC3in-C42 was discovered utilizing the hybridization of advantageous fragments, whose potency (IC50 = 7.6 nM) had been greatly improved compared with that of DC-LC3in-D5. LC3in-C42 inhibits Autophagy at the cellular level and its efficacy far exceeds that of DC-LC3in-D5. Thus far, LC3in-C42 stands as the most potent LC3A/B small molecule inhibitor. LC3in-C42 could serve as a powerful tool for LC3A/B protein and Autophagy research.

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