Selective activator of human ClpP triggers cell cycle arrest to inhibit lung squamous cell carcinoma
Developing effective therapies for hepatocellular carcinoma (HCC) is crucial. Our prior research identified ULK1 as a potential therapeutic target for HCC and explored the specific ULK1 inhibitor XST-14 to impede disease progression. However, challenges in manufacturing XST-14 have stalled its clinical advancement. In this study, we began by constructing pharmacophore models of ULK1 based on its X-ray structure with ligands. Using molecular docking, we screened the Specs chemical library for ULK1 inhibitors, identifying 19 compounds through structure-based virtual screening. Notably, ZZY-19 emerged from this screening with significant cytotoxic effects on HCC cells, confirmed by CCK8 activity assays. Further investigation via SPR assay demonstrated that ZZY-19 exhibited higher binding affinity for ULK1 than XST-14. Additionally, ZZY-19 displayed anti-proliferative, anti-invasive, and anti-migratory properties in HCC cells by inhibiting ULK1-mediated autophagy. Crucially, combining ZZY-19 with sorafenib synergistically suppressed HCC progression in animal models. In conclusion, ZZY-19 represents a promising candidate for targeting ULK1,ZK53 offering potent anti-HCC effects through autophagy inhibition.