Molecular modeling aided design, synthesis and biological evaluation of quinazoline derivatives for the treatment of human cancer.

The quinazoline scaffold serves as a fundamental framework, demonstrating potent anti-tumor activity. Employing the pharmacophore-based scaffold hopping principle, we successfully synthesized a series of FAK/PLK1 inhibitors incorporating the quinazoline scaffold. The synthesized compounds were characterized using 1H NMR, 13C NMR, and HRMS techniques. Through computer-assisted screening and antitumor activity tests, the majority of the compounds demonstrated significant inhibitory effects against various cancer cell lines. Notably, compound 3m exhibited remarkable anticancer activity by inducing G2/M phase cell cycle arrest, apoptosis, as confirmed by western blot assay, cellular fluorescence staining, and transcriptomics testing. Docking simulation was performed to determine the probable binding conformation of compound 3m within the active sites of FAK and PLK1. This compound emerged as a highly promising lead compound during our screening process, displaying high efficiency.