3‑Phenethyl-2-phenylquinazolin-4(3<i>H</i>)‑one Inhibits Breast Cancer Cell Motility, EnergyMetabolism,and Proliferation by Inactivating Phosphoinositide 3‑Kinase/ProteinKinase B and Epidermal Growth Factor Receptor Pathways

Marine-derived compounds hold great promise for cancer therapy, targeting various essential processes in cancer progression, such as apoptosis, metastasis, proliferation, and drug resistance. 3-Phenethyl-2-phenylquinazolin-4­(3<i>H</i>)-one (<b>1</b>) is a natural quinazolinone derivative extracted from the marine sediment-derived genus <i>Acremonium</i> sp. CNQ-049. This study explores the therapeutic effects and underlying mechanisms of <b>1</b> in breast cancer. Compound <b>1</b> significantly inhibited epithelial–mesenchymal transition by downregulating EMT-related transcription factors as well as cancer metabolism by reducing the expression of glycolytic enzymes. By targeting protein kinase B (AKT1) and epidermal growth factor receptor (EGFR), compound <b>1</b> decreased the expression of p-AKT, p-EGFR, p-STAT3, p-NF-κB, β-catenin, and estrogen receptor, along with their downstream targets c-Myc and cyclin-D1, thereby inhibiting breast cancer cell motility, proliferation, and energy metabolism. In an orthotopic mouse model of breast cancer, treatment with <b>1</b> effectively inhibited tumor growth and downregulated associated target genes <i>in vivo</i>. Compound <b>1</b> exerted potent anticancer activity against breast cancer (BC) cells <i>in vitro</i> and effectively inhibited tumor growth in an orthotopic mouse model. Overall, suppression of both EMT and reprogramming of cancer metabolism metabolic pathways by inactivating phosphoinositide 3-kinase (PI3K)/AKT and EGFR pathways suggested that <b>1</b> could be a potential therapeutic agent for BCs. Notably, <b>1</b> represents a promising therapeutic effect against hormone-dependent (ER-positive) BCs.