Eltrombopag Inhibited Liver Cancer by Enhancing SMYD4 Protein Degradationvia TRIP12 Ubiquitinase

Abstract According to prior studies, SET and MYND domain‐containing protein 4 (SMYD4) is involved in tumor progression and metastasis, representing a potential therapeutic target for tumors. However, no specific inhibitors or drugs targeting SMYD4 are currently available. In this study, molecular docking and molecular dynamics simulations were used to screen small molecule lead compounds binding to SMYD4 protein. CCK8 assay, colony formation assay, EdU assay were used to analyze the viability and proliferation of tumor cells. Flow cytometric analysis was used to evaluate cell apoptosis and cell cycle. Clorazepate, Ativan, Darifenacin and Eltrombopag were found to bind with SMYD4 with the highest probability and to meet the five principles of the drug class. Molecular dynamics simulations showed that Eltrombopag had the strongest binding capacity to SMYD4 protein. The functional analysis showed that Eltrombopag inhibited hepatocellular carcinoma cell proliferation and promoted apoptosis in vivo and in vitro at low density. Moreover, Eltrombopag enhanced ubiquitination of SMYD4 protein and promoted its degradation via thyroid hormone receptor interactor 12(TRIP12). These findings suggest that Eltrombopag is a potential inhibitor of SMYD4 protein, representing a novel leading compound for SMYD4 and applied for tumor treatment.