Coumarin-based dual kinase inhibitors targeting CDK6 and VEGFR-2: experimental and computational validation

A rational pharmacophore-guided strategy was employed to design and synthesize a series of novel coumarin derivatives as potential dual cyclin-dependent kinase 6 (CDK6) and vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. Following structural characterization, the synthesized compounds were evaluated for their anticancer activity against MCF-7, MDA-MB-231, HepG-2, and HCT-116 cancer cell lines, together with normal WI-38 and WISH cells. Among the tested derivatives, compound 7e exhibited the highest potency, with IC₅₀ values ranging from 3.80 to 6.35 µM, while demonstrating superior selectivity toward cancer cells compared with sorafenib. Enzymatic assays confirmed potent dual inhibition of VEGFR-2 (IC₅₀ = 0.3905 µM) and CDK6 (IC₅₀ = 0.3380 µM). Mechanistic studies revealed that compound 7e induced significant apoptosis, promoted S-phase cell cycle arrest, and effectively inhibited cell migration in HCT-116 cells. Computational studies, including molecular docking, molecular dynamics simulations, and binding free energy calculations, supported its stable interactions with both kinase targets. Furthermore, in silico ADMET analysis predicted favorable pharmacokinetic and safety profiles. Collectively, these findings identified compound 7e as a promising dual VEGFR-2/CDK6 inhibitor with potent and selective anticancer activity, warranting further preclinical investigation.