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.
Subject(s)
Antineoplastic Agents , Cell Proliferation , Proto-Oncogene Proteins , Triazoles , Humans , Triazoles/chemistry , Triazoles/pharmacology , Triazoles/chemical synthesis , Cell Proliferation/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/antagonists & inhibitors , Structure-Activity Relationship , Molecular Structure , Drug Screening Assays, Antitumor , Sulfonic Acids/chemistry , Sulfonic Acids/pharmacology , Sulfonic Acids/antagonists & inhibitors , Cell Line, Tumor , Esters/chemistry , Esters/pharmacology , Esters/chemical synthesis , Proteasome Endopeptidase Complex/metabolism , Proteasome Endopeptidase Complex/chemistry , Dose-Response Relationship, Drug , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , BenzenesulfonatesABSTRACT
Background: Gankyrin is an ankyrin-repeat protein that promotes cell proliferation, tumor development and cancer progression when overexpressed. Aim: To design and synthesize a novel series of gankyrin-binding small molecules predicated on a 2,5-pyrimidine scaffold. Materials & methods: The synthesized compounds were evaluated for their antiproliferative activity, ability to bind gankyrin and effects on cell cycle progression and the proteasomal degradation pathway. Results: Compounds 188 and 193 demonstrated the most potent antiproliferative activity against MCF7 and A549 cells, respectively. Both compounds also demonstrated the ability to effectively bind gankyrin, disrupt proteasomal degradation and inhibit cell cycle progression. Conclusion: The 2,5-pyrimidine scaffold exhibits a novel and promising strategy for binding gankyrin and inhibiting cancer cell proliferation.