Discovery of new quinazolin-4-ones as dual EGFR/c-SRC inhibitors with potential to overcome bypass-mediated resistance in cancer.

This study reports the rational design, synthesis, and preliminary evaluation of a novel series of quinazolin-4-one derivatives. These compounds were developed as potential dual inhibitors of EGFR and c-SRC kinases to explore their utility in addressing bypass-related signaling in cancer cells. Through systematic optimization, compound 9b emerged as a lead candidate, demonstrating potent and balanced enzymatic inhibition with IC50 values of 0.057 μM (EGFR) and 0.073 μM (c-SRC). To our knowledge, this represents an unprecedented achievement in the development of dual EGFR/c-SRC inhibitors with this potency profile. In cellular assays, 9b exhibited significant antiproliferative activity, induced G0/G1 cell cycle arrest, and triggered apoptosis via modulation of p53, Bax, and Bcl-2 expression. Molecular docking and dynamics simulations confirmed stable binding modes within both kinase active site key amino acids, forming critical hinge-region interactions. Computational ADMET predictions further support its favorable drug-like properties. Collectively, 9b represents a promising dual-targeted therapeutic lead worthy of advanced preclinical development.