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

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Structure-Based Design and Discovery of a Potent and Cell-Active LC3A/B Covalent Inhibitor
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-15 , 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,

3,

4,

6,

7}

Affiliation

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.

中文翻译：

基于结构的设计和发现有效的细胞活性 LC3A/B 共价抑制剂

自噬是真核生物中高度保守的细胞稳态维持机制。微管相关蛋白轻链 3 (LC3) 在自噬中发挥着至关重要的作用。它与其他蛋白质具有多对蛋白质-蛋白质相互作用（PPI），这些 PPI 对自噬体形成的调节和自噬底物的招募有影响。在我们之前的工作中，鉴定了一种可以抑制LC3A/B PPI的小分子共价抑制剂DC-LC3in-D5 ，但缺乏对构效关系（SAR）的详细研究。在此，利用有利片段的杂交发现了新分子LC3in-C42 ，其效价(IC ₅₀ = 7.6 nM)与DC-LC3in-D5相比有很大提高。 LC3in-C42在细胞水平上抑制自噬，其功效远远超过DC-LC3in-D5 。迄今为止， LC3in-C42是最有效的 LC3A/B 小分子抑制剂。 LC3in-C42可以作为 LC3A/B 蛋白和自噬研究的强大工具。

更新日期：2024-07-15

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