INVESTIGATION OF INTERACTION OF CABOZANTINIB WITH TOPOISOMERASE ENZYMES

DNA topoisomerase enzymes regulate the vital activities of the cell and therefore play a critical role in the cell. Since they have been involved in intracellular events such as replication and transcription, they have been targeted by anti-cancer drugs. In our study, we investigated the interaction of topoisomerase enzymes with a new tyrosine kinase inhibitor, Cabozantinib. Protein kinases have the most important role in cell signaling, and tyrosine kinases destroy cancer cells by apoptosis. When protein kinases receive the appropriate signal in cell signal transduction, they add phosphate to serine, tyrosine and histidine aminoacids in other proteins and thereby alters the enzyme activity in the target protein and its association with other proteins. The cell undergoes apoptosis and dies, in case of not receiving signaling from the outside.

In this study, the topoisomerase enzyme inhibition properties of Cabozantinib have been investigated. Considering the mechanism of action of Cabozantinib, we focused on the possibility that this agent would also inhibit topoisomerase enzymes. The interaction of Cabozantinib and topoisomerase IIa enzymes was investigated with the help of Autodock, Autodock Vina and Pyrx docking programs. In line with the approximate values obtained, it was observed that Cabozantinib gave a close binding affinity with Etoposide, a known topoisomerase II enzyme inhibitor, which we used as a control compound. When the docking results of Cabozantinib structure were examined with the Autodock Vina program, the RMSD value was determined as 3.075 Ǻ. In compared with etoposide, it gave similar binding energie values. The interactions of this compound with topoisomerase IIa enzymes were investigated by subjecting it to topoisomerase enzyme activity tests, in vitro. Our data shows that Cabozantinib inhibits topoisomerase II enzyme in vitro conditions. Further analysis are required to evaluate this chemical as anti cancer agent.