Aug 2026· Journal of Computational Biophysics and Chemistry· 0 citations
TL;DR
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.
Abstract
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.
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
Mechanistic studies revealed that compound 7e induced significant apoptosis, promoted S-phase cell cycle arrest, and effectively inhibited cell migration in HCT-116 cells, identifying him as a promising dual VEGFR-2/CDK6 inhibitor with potent and selective anticancer activity.
Hazem Elkady, Walid E. Elgammal, I. Eissa et al.· RSC Advances· 0 citations
The Epidermal Growth Factor Receptor (EGFR) remains validated therapeutic goalfor Breast Cancer, especially because of its function in signalling pathways that promote tumor development and viability. In the current investigation, a series of newly designed amino quinoxaline derivatives (QN1–QN10) were investigated for their potential EGFR inhibitory and anticancer activities using an integrated in silico and in vitro approach. Molecular docking studies were carried out using Schrödinger Maestro to rate the binding kineticsof the designed compounds with the EGFR tyrosine kinase domain (PDB ID: 4HJO), employing erlotinib as the reference standard. The docking protocol was validated by redockingerlotinib into the active site, confirming the reliability of the methodology. Glide extra-precision (XP) docking revealed favourable binding orientations of selected derivatives within the EGFR catalytic pocket. The cytotoxicity of selected compounds (QN2, QN4, and QN8) was further calculated through MTT assay for human breast cancer cell line MCF-7. The results proved that the cell longevity was decreased in a concentration-dependent way, with erlotinib exhibiting the greatest potency (LC50 = 18.47 µg/mL). Among the synthesized derivatives, QN4 showed relatively higher activity (LC50 = 121.52 µg/mL) than QN2 and QN8.Statistical analysis proved the relevance of the cytotoxic effects observed (p < 0.0001). Overall, the combined computational and biological findings suggest that amino quinoxaline scaffolds indicate potential avenues for enhanced optimization as EGFR-targeted anticancer drugs.
Abitha H, D. Kumudha· Oriental Journal of Chemistr...· 0 citations
Vascular endothelial growth factor receptor 2 (VEGFR-2) is a principal regulator of tumor progression and angiogenesis, which makes it an attractive target for developing and creating anticancer agents. A series of sulfonamide-derived compounds (K1-K5) were designed and evaluated for their ability to inhibit VEGFR-2 and for their cytotoxic activity against HCT-116 (colon), HepG-2 (liver), MCF-7 (breast) human cancer cells, and WI-38 (normal) fibroblasts. All of the compounds produced significant inhibition of VEGFR-2, with IC50values ranging from 0.0917 ± 0.028 µM (K5) to 1.2007 ± 0.013 µM (K1), relative to Sorafenib (IC50 = 0.0525 ± 0.017 µM). The most promising compound was K4, which produced potent inhibition of VEGFR-2 (IC50 = 0.1717 ± 0.027) and the highest selectivity index (SI) of all tested compounds: 25.6 (HCT-116), 14.8 (HepG-2), and 17.0 (MCF-7). In contrast to Sorafenib, whose Selectivity Index (SI) values range between 2.1 and 4.9, the SI values of both Vinblastine and Doxorubicin are less than 2.0 across these particular cell lines. This suggests that K4 has 12 times greater selectivity than Sorafenib and over 25 times greater selectivity than traditional chemotherapeutics. The increased selectivity of K4 can be attributed to the incorporation of a urea-linked sulfonamide moiety, which allows for the formation of hydrogen bonds and minimizes nonspecific hydrophobic interactions. Collectively, these data will demonstrate the importance of designing sulfonamide analogues with optimal structural characteristics to identify effective and specific VEGFR-2 inhibitors and that K4 represents a potentially important candidate for continued preclinical development.
Ahmed Wheed Radhi, Hayder Ghanim Chfat, Zahraa Sabbar Omarn et al.· Future Medicinal Chemistry· 0 citations
Acquired resistance to anti-angiogenic therapy often arises via erb-b2 receptor tyrosine kinase 3 (ErbB3)-mediated compensatory signalling, necessitating dual vascular endothelial growth factor receptor 2 (VEGFR2)/ErbB3 inhibitors that can simultaneously block both pathways to overcome resistance. Herein, we adopted a multi-scale computational strategy integrating density functional theory (DFT), molecular docking, and molecular dynamics (MD) simulations to screen and characterize dual-target candidates from our in-house compound library. A novel quinoline derivative, 7-(benzyloxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyquinolin-4-amine (E5), was successfully identified as a potent dual-target inhibitor with favourable dual-target binding potency. Experimental validation using in vitro kinase assays confirmed that E5 potently inhibits VEGFR2 and ErbB3, with IC50 values of 0.42 μM and 0.04 μM, respectively. Our DFT calculations revealed that E5 adopts a flat conformation (20.05 × 10.61 × 6.02 ų) with balanced electrostatic potential and the lowest LUMO energy (-0.88 eV) among reference compounds, enabling it to adapt to the distinct ATP-binding pockets of VEGFR2 and ErbB3 with different gatekeeper residues. High-precision molecular docking identified target-specific binding modes: van der Waals and hydrophobic interactions dominate in the E5-VEGFR2 association, while ErbB3 engages with E5 via hydrogen bonding to THR768, sulfur-π interaction with CYS721, and π-π stacking with PHE834. 200 ns all-atom MD simulations further confirmed the stability of E5-VEGFR2 and E5-ErbB3 complexes, with MM/PBSA binding free energies of -32.41 kcal/mol (VEGFR2) and -31.22 kcal/mol (ErbB3), both predominantly contributed by van der Waals interactions. This work demonstrates the reliability and efficiency of computational approaches for the rational screening and discovery of dual-target kinase inhibitors, highlighting E5 as a promising lead compound that warrants further investigation to address clinical anti-angiogenic therapeutic resistance.
Xin-Yu Zhou, Ya-Nan Yuan, Chaochun Wei et al.· Computational biology and ch...· 0 citations
Structural–activity relationship analysis revealed the importance of the TZD core, electron-rich aromatic moieties, and balanced lipophilicity for enhanced anticancer activity, identifying TZD hybrids as promising EGFR-targeted anticancer leads.
Rajyalaxmi Injamuri, D. Makula· International journal of res...· 0 citations
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