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

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: We developed a novel PROTAC YX-112 of celastrol, which was extremely sensitive to the triple-negative breast cancer MDA-MB-231 cells, with an IC Conclusion: This study provides new insights into the derivation of celastrol and its molecular mechanisms of action.