Structure-Based Virtual Screening towards the Discovery of Novel ULK1 Inhibitors with Anti-HCC Activities |
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Authors: | Yang Gao Ziying Zhou Tingting Zhang Situ Xue Ke Li Jiandong Jiang |
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Affiliation: | Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; (Y.G.); (Z.Z.); (T.Z.); (S.X.); (K.L.) |
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Abstract: | There is an urgent need to develop new effective therapies for HCC. Our previous study identified ULK1 as the potential target for HCC therapy and screened the compound XST-14 as a specific inhibitor of ULK1 to suppress HCC progression. However, the poor manufacturability of XST-14 impeded the process of its clinical translation. In this study, we first generated pharmacophore models of ULK1 based on the X-ray structure of UKL1 in complex with ligands. We then screened the Specs chemical library for potential UKL1 inhibitors. By molecular docking, we screened out the 19 compounds through structure-based virtual screening. Through CCK8 activity screening on HCC cells, we found that ZZY-19 displayed obvious cell killing effects on HCC cells. SPR assay indicated that ZZY-19 had a higher binding affinity for ULK1 than XST-14. Moreover, ZZY-19 induced the effects of anti-proliferation, anti-invasion and anti-migration in HCC cells. Mechanistically, ZZY-19 induces autophagy inhibition by reducing the expression of ULK1 on HCC cells. Especially, the combination of ZZY-19 with sorafenib synergistically suppresses the progression of HCC in vivo. Taken together, ZZY-19 was a potential candidate compound that targeted ULK1 and possessed promising anti-HCC activities by inhibiting autophagy. |
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Keywords: | autophagy hepatocellular carcinoma ULK1 virtual screening |
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