CVT-313

The over-expression of cyclin-dependent kinase 2 is related to multiple cancers, which has led them to be a widely researched topic for nearly two decades. The prime focus of the present research is to design new potent and specific inhibitors against CDK2 to suppress cancer cell proliferation. In this study, we have chosen Flavopiridol, SU9516, and CVT-313 as standard inhibitors to compare with in-house synthesized pyrrolone-fused benzosuberene (PBS) compounds. We scrutinized Ligand2 as a selective inhibitor of CDK2 without off-target binding (CDK1 and CDK9) based on ligand efficiency and binding affinity. Interpretation of dynamic simulations and binding free energy studies unveiled that Ligand2 has a stable and equivalent free energy to standard inhibitors. These outcomes led towards positioning a potential natural molecule as selective inhibitor for CDK2 with low side effects.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers with high mortality and poor prognosis, and the investigation on new approaches and effective drugs for HCC therapy is of great significance. In our study, we demonstrate that treatment with cinobufagin, a natural compound isolated from traditional chinese medicine Chansu, reduces proliferation and the colony formation capacity of the human hepatoma cells in vitro, in addition, cinobufagin induces mitotic arrest in human hepatoma cells. The results of a network pharmacology-based analysis show that EGFR, MAPK1, PTK2, CDK2, MAPK3, ESR1, CDK1, PRKCA, AR, and CSNK2A1 are the key targets involved in the anti-tumor activities of cinobufagin, additionally, several signaling pathways such as proteoglycans in cancer, pathways in cancer, HIF-1 signaling pathway, VEGF signaling pathway, ErbB signaling pathway, and PI3K-AKT signaling pathway are identified as the potential pathways involved in the inhibitory effects of cinobufagin against HCC. Furthermore, at the molecular level, we find that cinobufagin decreases EGFR expression and CDK2 activity in human hepatoma cells. Inhibition of EGFR or CDK2 expression could not only suppress the growth of tumor cells but also enhance the inhibitory effects of cinobufagin on the proliferative potential of human hepatoma cells. We also demonstrate that EGFR positively regulates CDK2 expression. Furthermore, EGFR inhibitor gefitinib or CDK2 inhibitor CVT-313 synergistically enhances anticancer effects of cinobufagin in human hepatoma cells. Taken together, these findings indicate that cinobufagin may exert antitumor effects by suppressing EGFR-CDK2 signaling, and our study suggests that cinobufagin may be a novel, promising anticancer agent for the treatment of HCC.