Anticancer potential of nicotinonitrile derivatives as PIM-1 kinase inhibitors through apoptosis: in vitro and in vivo studies

Abstract

Cytotoxicity of a series of nicotinonitrile-based derivatives with the molecular target and apoptosis activity against PC-3 cells was described. Compound 7b exhibited remarkable cytotoxicity against MCF-7 and PC-3 cells with IC₅₀ values of 3.58 μM and 3.60 μM, respectively. Interestingly, compounds 4k and 7b had potent PIM-1 kinase inhibition with IC₅₀ values of 21.2 nM and 18.9 nM, respectively, with inhibition of 92.7 and 96.4% compared to Staurosporine (IC₅₀ = 16.7 nM, with 95.6% inhibition). Moreover, compound 7b significantly activated apoptosis in PC-3 cells, increasing the apoptotic cell death, increasing total apoptosis by 34.21% compared to 0.9% in control cells, and arresting the cell cycle at the G1 pahse. In vivo model of SEC-bearing mice confirmed the anticancer activity of compound 7b by having 42.9% compared to the 5-FU treatment of 54.2%; it maintained the physiological activity of hematological and biochemical parameters. Molecular docking effectively sheds insight into the mechanism of PIM-1 kinase inhibition by revealing the binding interactions between the lead chemical 7b and the PIM-1 protein. The results showed that compound 7b showed promise as a chemotherapeutic drug targeting PIM-1 for the treatment of breast cancer.