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.
Hazem Elkady, Walid E. Elgammal, I. Eissa et al.· RSC Advances· 0 citations
The development of selective vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors remains a promising strategy for anticancer therapy targeting tumor angiogenesis. In the study at hand, a novel benzanilide-based derivative, ACEB-Cl, was rationally designed by assimilating fundamental pharmacophoric characteristics essential for VEGFR-2 inhibition. ACEB-Cl was evaluated using a comprehensive approach that combined computational modeling, synthesis, and in vitro biological assessment. Density functional theory (DFT) calculations revealed a favorable electronic profile, with distinct nucleophilic and electrophilic regions that could support potential interactions within the VEGFR-2 binding pocket. Docking and molecular dynamics (MD) simulations suggested stable binding of ACEB-Cl within the ATP-binding pocket, supported by strong hydrophobic interactions and favorable binding free energy (ΔG = −63.21 kcal/mol). Following synthesis, ACEB-Cl confirmed potent anti-VEGFR-2 activity in an ELISA-based assay (IC50 = 0.086 0.002 M), showing higher potency than sorafenib. Western blot analysis further confirmed significant downregulation of phosphorylated VEGFR-2 in MDA-MB-231 cells. In vitro cytotoxicity studies revealed selective anticancer activity, with reduced toxicity toward normal Vero cells and favorable selectivity indices. Mechanistically, ACEB-Cl triggered G0/G1 phase arrest and significantly increased apoptotic cell death, highlighting its ability to suppress cancer cell proliferation. Additionally, ADMET and toxicity estimations indicated a balanced pharmacokinetic and safety profile, with improved solubility, acceptable absorption, and reduced toxicity risks compared to sorafenib. Overall, this integrated study pinpointed ACEB-Cl as a promising VEGFR-2targeted anticancer lead compound with strong inhibitory potency, and a clearly defined mechanism of action, supporting its progression for further improvement.
A. Metwaly, I. Eissa, Walid E. Elgammal et al.· Journal of Computational Bio...· 0 citations
Findings identify compound 7e as a promising VEGFR-2-targeted anticancer lead with strong enzymatic inhibition, potent cytotoxicity, and a well-supported mechanistic profile integrating experimental and computational evidence.
A. Metwaly, Walid E. Elgammal, I. Eissa et al.· RSC Advances· 0 citations