2. Academic Validation
  3. Structure-Based Design and Discovery of a Potent and Cell-Active LC3A/B Covalent Inhibitor

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

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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