Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Molecules. 2022 Apr 19;27(9):2627. doi: 10.3390/molecules27092627.
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.
目前迫切需要开发新的有效治疗 HCC 的方法。我们之前的研究确定 ULK1 是 HCC 治疗的潜在靶点，并筛选了化合物 XST-14 作为 ULK1 的特异性抑制剂来抑制 HCC 进展。然而，XST-14 的制造工艺较差，阻碍了其临床转化。在本研究中，我们首先根据 ULK1 与配体复合物的 X 射线结构生成了 ULK1 的药效团模型。然后，我们从 Specs 化学库中筛选潜在的 ULK1 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 19 种化合物。通过 HCC 细胞 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 测定表明，ZZY-19 与 XST-14 相比，对 ULK1 具有更高的结合亲和力。此外，ZZY-19 可诱导 HCC 细胞增殖、侵袭和迁移抑制。在机制上，ZZY-19 通过降低 HCC 细胞上 ULK1 的表达诱导自噬抑制。特别是，ZZY-19 与索拉非尼联合使用可协同抑制 HCC 在体内的进展。总之，ZZY-19 是一种潜在的候选化合物，可通过抑制自噬靶向 ULK1，并具有有前途的抗 HCC 活性。
