Imidazo[1,2‐a]Quinoxaline‐2‐Carbonitrile Derivative (RA‐22) Inhibits Self‐Renewal and Growth of Cancer Stem and Cancer Cells via Downregulating AKT Pathway

Abstract

AbstractEGFR activation in colorectal and breast cancer stimulates downstream pathways like Ras/Raf/MEK/ERK and PI3 K/Akt, fostering cell proliferation, invasion, metastasis, and therapy resistance, underscoring its significance as a therapeutic target in both cancers. In the present work, we rationally designed (E)‐4‐methyl‐1‐((3‐oxo‐1‐phenylbutyl)amino)‐4‐styryl‐4,5‐dihydroimidazo[1,2‐a]quinoxaline‐2‐carbonitrile (RA‐22) as EGFR inhibitor. Our research investigates the role of RA‐22 as a target molecule for EGFR, exploring its anticancer potential and mechanism of action across breast cancer and colorectal cancer cell lines. The in‐vitro studies showed its cytotoxic response towards MDA‐MB‐231 and HCT‐116 and its inhibitory effect on cancer stem cells in mammosphere/spheroid culture. The compound downregulates the oncogenic signalling proteins like STAT‐3, AKT, PAN‐AKT, and ERK and also reduces the expression of the anti‐apoptotic protein Bcl‐2 and increases the apoptotic proteins like Cleaved‐PARP, Cleaved‐Caspase‐3, and Cleaved‐Caspase‐9.