Aug 2026· Biochemical Pharmacology· pp.
118353
· 0 citations· 101 references
Medicine
TL;DR
Virtual screening of 39,442 natural products from the ZINC natural product library, coupled with molecular docking and molecular dynamics simulations to evaluate the binding stability of candidate compounds, identified NAT-6-321056 as a highly promising modulator of VEGFR2 signaling and represents a viable candidate for cancer therapy.
Abstract
Vascular endothelial growth factor receptor 2 (VEGFR2) is a master regulator of angiogenesis and cancer progression. However, current VEGFR2 modulator face significant challenges, including off-target toxicity and acquired resistance, underscoring the urgent need for novel therapeutic agents with improved efficacy and safety profiles. Here, we reported that virtual screening of 39,442 natural products from the ZINC natural product library, coupled with molecular docking and molecular dynamics (MD) simulations to evaluate the binding stability of candidate compounds, identified NAT-6-321056 as a highly promising modulator of VEGFR2 signaling. Biological evaluations demonstrated that NAT-6-321056 exerted potent inhibition on the growth of a broad spectrum of cancer cells, including both solid tumors and hematological malignancies. In EA.hy 926 endothelial cells and SK-N-DZ neuroblast cells, the compound significantly suppressed proliferation, migration, and invasion. Microscale thermophoresis (MST) confirmed direct binding of NAT-6-321056 to VEGFR2 with favorable affinity. Kinase profiling against a panel of 33 kinases indicated that NAT-6-321056 exhibited a multi-kinase modulation profile. Mechanistic studies revealed that NAT-6-321056 suppressed the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and was associated with reduced VEGFR2 phosphorylation and attenuation of the downstream ERK/JNK/AKT signaling pathways. Moreover, NAT-6-321056 exhibited robust in vivo anti-angiogenic effects in both the chick chorioallantoic membrane (CAM) assay and transgenic zebrafish vascular fluorescence imaging models. Computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction suggested acceptable drug-like properties. Collectively, these findings demonstrated that NAT-6-321056 is a promising modulator of VEGFR2 signaling with potent anti-angiogenic activity and represents a viable candidate for cancer therapy.
INTRODUCTION
Inhibiting tumor angiogenesis is a recognized anticancer strategy. VEGFR2 is a key driver of pathological angiogenesis via VEGF signaling. Natural chalcones can target VEGFR2 but are limited by weak activity and low yield.
OBJECTIVE
To design and synthesize novel chalcones as VEGFR2 inhibitors to suppress tumor angiogenesis, thereby offering a new anti-angiogenic strategy for colorectal cancer (CRC).
METHODS
A series of novel chalcones was synthesized, and compound 27j, bearing a bis-Michael acceptor moiety, was selected. Its binding affinity to VEGFR2 was assessed by surface plasmon resonance (SPR), and a kinase selectivity profile was generated. The effects on VEGFR2 activation and downstream signaling pathways were analyzed. Anti-angiogenic effects and inhibition of CRC growth were evaluated through in vitro experiments, in vivo animal studies, and patient-derived xenograft (PDX) models. Pharmacokinetics, ADME, and acute/chronic toxicity were characterized.
RESULTS
Compound 27j demonstrated some binding affinity for VEGFR2 in SPR assays. However, it did not exhibit significant inhibitory activity in enzymatic kinase assays, suggesting that its mechanism of action may differ from classical ATP competition. In vitro and in vivo studies confirmed that 27j effectively inhibits key angiogenetic processes and interferes with VEGFR2 activation and its downstream signaling. In PDX models, angiogenesis was inhibited in tumors from the 27j-treated group, and there was a trend toward delayed CRC growth.
CONCLUSION
Compound 27j represents a novel VEGFR2 inhibitor whose mechanism may involve non-classical rather than direct ATP competition. It exhibits promising anti-angiogenic and anti-tumor activity in CRC models, supporting its further investigation as a promising lead compound for anti-tumor angiogenesis therapy.
Kun Wang, Rui Wang, Kai Kong et al.· Journal of Advanced Research· 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
EphA2 (ephrin type-A receptor 2) is a representative member of the Eph receptor tyrosine kinase family and is frequently overexpressed in a broad spectrum of malignant tumors. It participates in regulating tumor cell proliferation, migration, invasion, and angiogenesis through ligand-dependent and ligand-independent signaling pathways, thus emerging as a promising target for anticancer drug discovery. In recent years, extensive research has been carried out toward the discovery and optimization of small-molecule EphA2 inhibitors, covering a variety of chemical scaffolds with distinct mechanisms of action. This review provides a comprehensive overview of the research progress of EphA2-targeted small-molecule inhibitors reported to date. We systematically summarize their representative chemical scaffolds, structure-activity relationships, binding modes, and pharmacological profiles, and highlight the current challenges in selectivity, pharmacokinetic properties, and clinical translation. This review is expected to offer valuable guidance for the rational design and optimization of next-generation EphA2-targeted therapeutics.
Liyan Yang, Jun He, Wenjing Xiao et al.· European journal of medicina...· 0 citations
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
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
Overall, the simulations indicate persistent peptide-receptor association and stable structural behavior of the complexes at the computational level, however, molecular docking and molecular dynamics simulations do not demonstrate functional inhibition of EGFR, ERBB2, or VEGFR-3, nor do they confirm anticancer efficacy.
Shehla Javaid, Zahid Mushtaq, A. Jamil et al.· Scientific Reports· 0 citations
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