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Abstract：
Liver cancer is a complex disease that involves various oncoproteins and the inactivation of tumor suppressor proteins (TSPs). Gankyrin is one such oncoprotein, first identified in human hepatocellular carcinoma, that is known to inactivate multiple TSPs, leading to proliferation and metastasis of tumor cells. Despite this, there has been limited development of small molecule gankyrin binders for the treatment of liver cancer. In this study, we are reporting the structure-based design of gankyrin-binding small molecules which inhibit the proliferation of HuH6 and HepG2 cells while also increasing the levels of certain TSPs, such as Rb and p53. Interestingly the first molecule to exhibit inhibition by 3D structure stabilization is seen. These results suggest a possible mechanism for small-molecule inhibition of gankyrin and demonstrate that gankyrin is a viable therapeutic target for the treatment of liver cancer.
摘要：
肝癌是一种复杂的疾病，涉及各种癌蛋白和肿瘤抑制蛋白（TSP）的失活。Gankyrin就是这样一种癌蛋白，首次在人类肝细胞癌中发现，已知会使多个TSP失活，导致肿瘤细胞增殖和转移。尽管如此,用于治疗肝癌的小分子gankyrin结合剂的开发有限。在这项研究中,我们报道了基于结构的gankyrin结合小分子的设计，这些小分子抑制HuH6和HepG2细胞的增殖，同时也增加某些TSP的水平，如Rb和p53。有趣的是,观察到第一个通过3D结构稳定化表现出抑制作用的分子。这些结果表明小分子抑制gankyrin的可能机制，并证明gankyrin是治疗肝癌的可行治疗靶标。
