Quinoxalinone substituted pyrrolizine (4h)-induced dual inhibition of AKT and ERK instigates apoptosis in breast and colorectal cancer by modulating mitochondrial membrane potential

AKT and ERK 1/2 play a pivotal role in cancer cell survival, proliferation, migration, and angiogenesis. Therefore, AKT and ERK 1/2 are considered crucial targets for cancer intervention. In this study, we envisaged the role of AKT and ERK signaling in apoptosis regulation in presence of compound 4h, a novel synthetic derivative of quinoxalinone substituted spiropyrrolizines exhibiting substantial antiproliferative activity in various cancer cell lines. Structurally 4h is a spiropyrrolizine derivative. Molecular docking analysis revealed that compound 4h shows strong binding affinity with AKT-1 (-9.5 kcal/mol) and ERK2 (-9.0 kcal/mol) via binding at allosteric sites of AKT and active site of ERK2. The implications of 4h binding with these two survival kinases resulted in the obstruction for ATP binding, hence, hampering their phosphorylation dependent activation. We demonstrate that 4h mediated apoptotic induction via disruption in the mitochondrial membrane potential of MCF-7 and HCT-116 cells and 4h-mediated inhibition of survival pathways occurred in a wild type PTEN background and is diminished in PTEN- /-cells. In 4T1 mammary carcinoma model, 4h exhibited pronounced reduction in the tumor size and tumor volume at significantly low doses. Besides, 4h reached the highest plasma concentration of 5.8 & mu;M within a period of 1 h in mice model intraperitoneally. Furthermore, 4h showed acceptable clearance with an adequate elimination half-life and satisfactory pharmacokinetic behaviour, thus proclaiming as a potential lead molecule against breast and colorectal cancer by specifically inhibiting simultaneously AKT and ERK1/2 kinases.

Automated summary

This study demonstrates that compound 4h binds to AKT-1 and ERK2, inhibiting their activation by blocking ATP binding, leading to apoptosis induction by disrupting mitochondrial membrane potential. It also shows promising anti-tumor activity in mouse models and cancer cells, and exhibits satisfactory pharmacokinetic behavior, making it a potential lead molecule for breast and colorectal cancer treatment by targeting AKT and ERK1/2 kinases simultaneously.