Structure-Based Virtual Screening towards the Discovery of Novel ULK1 Inhibitors with Anti-HCC Activities.
Structure-Based Virtual Screening towards the Discovery of Novel ULK1 Inhibitors with Anti-HCC Activities.
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基于结构的虚拟筛选，发现具有抗 HCC 活性的新型 ULK1 抑制剂
DOI：
10.3390/molecules27092627
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发表时间：
2022-04-19
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--
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迫切需要开发针对 HCC 的新有效疗法。我们前期的研究将ULK1确定为HCC治疗的潜在靶点，并筛选出化合物XST-14作为ULK1的特异性抑制剂来抑制HCC进展。然而，XST-14的可制造性较差，阻碍了其临床转化进程。在本研究中，我们首先根据UKL1与配体复合物的X射线结构生成了ULK1药效团模型。然后我们筛选了 Specs 化学库中潜在的 UKL1 抑制剂。通过分子对接，我们通过基于结构的虚拟筛选筛选出了19个化合物。通过对HCC细胞的CCK8活性筛选，我们发现ZZY-19对HCC细胞表现出明显的细胞杀伤作用。 SPR分析表明ZZY-19对ULK1的结合亲和力高于XST-14。此外，ZZY-19还诱导HCC细胞抗增殖、抗侵袭和抗迁移作用。从机制上讲，ZZY-19 通过降低 HCC 细胞上 ULK1 的表达来诱导自噬抑制。特别是，ZZY-19与索拉非尼的组合可协同抑制体内HCC的进展。综上所述，ZZY-19 是一种潜在的候选化合物，它靶向 ULK1，并通过抑制自噬而具有良好的抗 HCC 活性。
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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