YX-112, a novel celastrol-derived PROTAC, inhibits the development of triple-negative breast cancer by targeting the degradation of multiple proteins

作者：Yongxue Gu, Mengmeng Yang, Wenbin Wang, Li-Hua Li, Ying Ma, Wen‐Shan Liu, Qiang Zhao · 发表于：Frontiers in Pharmacology · 年份：2025 · DOI：10.3389/fphar.2025.1571135 · 被引用次数：5 · 研究领域：Natural Compounds in Disease Treatment、Protein Degradation and Inhibitors、Ubiquitin and proteasome pathways

Background: Celastrol is an effective component of the plant Tripterygium wilfordii Hook. f., which has a high inhibitory effect on triple-negative breast cancer. However, the therapeutic window of celastrol is narrow, and as a multi-target drug, its mechanism of action in triple-negative breast cancer is not very clear. Therefore, developing new celastrol derivatives has become an urgent task. Method: In this work, we apply the PROTAC strategy to design and synthesis novel celastrol derivative. The antiproliferative activity of compound YX-112 against various types of cells was detected by CCK8 method. DIA-based quantitative proteomics, Western blot was used to explore the mechanism of compound YX-112 on triple-negative breast cancer MDA-MB-231 cells. Finally, the binding mode between compound YX-112 and target protein was predicted through molecular docking. Results: value of 0.32 ± 0.04 μM, and its antiproliferative activity was 3 times that of celastrol. Subsequently, through DIA-based quantitative proteomics and Western blot validation experiments, it was found that YX-112 could target the degradation of CHEK1 and PIK3R2 proteins in MDA-MB-231 cells in a ubiquitin-proteasome dependent manner, indicating that it could be used as a degrader of CHEK1 and PIK3R2 proteins. Additionally, YX-112 could effectively inhibit the expression levels of CDK4 and p-AKT, and its inhibitory effect was stronger than that of celastrol. Finally, molecular docking predicted the binding mode b...