Discovery of chromone-derived EGFR inhibitors as potent apoptosis inducers in cancer: In vitro and in vivo insights.
TL;DR
Compound 4v emerged as a leading candidate, showing EGFR kinase inhibitory activity comparable to Erlotinib, and computational analysis of 4v and EGFR molecular binding suggests that it serves as a superior binder to the inactive EGFR conformation.
Abstract
Chromone derivatives are acknowledged as a privileged scaffold, recognized for their diverse pharmacological activities, including anti-cancer properties, although comprehensive investigations in this domain have been limited. This research addresses the design, synthesis, and biological evaluation of a new series of C-2 anilinated chromone derivatives. Compounds 4v, 4x, and 4y exhibited significant in vitro cytotoxicity against hepatocellular carcinoma (HepG-2) and breast adenocarcinoma (MCF-7) cell lines. Importantly, all three compounds exceeded the cytotoxicity of Erlotinib against MCF-7 and HepG-2 cancer cells. Compound 4v emerged as a leading candidate, showing EGFR kinase inhibitory activity (IC50 = 60.7 nM) comparable to Erlotinib. It prompted cellular apoptosis and initiated cell cycle arrest at the G2/M phase. Mechanistic studies indicated that compound 4v upregulated essential pro-apoptotic factors, including P53, Bax, PUMA, and caspases-7, -8, and -9. In vivo experiments utilizing a xenograft SEC model demonstrated similar tumor growth inhibition and volume reduction between 4v and erlotinib. Computational analysis of 4v and EGFR molecular binding, considering both the active (PDB ID: 1M17) and inactive (PDB ID: 4HJO) forms, suggests that it serves as a superior binder to the inactive EGFR conformation. These results collectively underscore C-2 anilinated chromone derivatives, particularly 4v as a lead, as promising candidates for the advancement of effective anti-cancer therapeutics.