article · Journal of Enzyme Inhibition and Medicinal Chemistry
A library of modified chemical compounds was evaluated to discover new VEGFR-2 inhibitors for potential cancer treatment. Following computational docking, toxicity, and drug-likeness evaluations, four promising candidates were synthesised and tested in laboratory assays against VEGFR-2 and two cancer cell lines. Three candidates, named A-1, C-6, and D-1, displayed effective VEGFR-2 inhibition. Notably, compound D-1 demonstrated cytotoxic activity against HCT-116 cancer cells that was roughly twice that of the established drug sorafenib. Further testing revealed that compound D-1 arrested the cell cycle at the pre-G1 and G2-M phases, triggered both early and late apoptosis, and altered key apoptotic markers by increasing caspase-8 and BAX while reducing Bcl-2. Compound D-1 also lowered levels of inflammatory cytokines TNF-alpha and IL6, with its stability corroborated by 100-nanosecond molecular dynamics simulations.
VEGFR-2 is a primary therapeutic target in cancer due to its role in tumour blood vessel development and cell proliferation. Identifying new small molecules that are more potent than existing drugs like sorafenib, while also suppressing inflammatory signals and driving programmed cancer cell death, provides valuable starting points for the design of improved oncology therapeutics.
This work is relevant to pharmaceutical companies and medicinal chemistry programmes developing targeted oncology treatments. The compounds serve as early-stage drug candidates targeting VEGFR-2. Because the findings are derived exclusively from computational screening, chemical synthesis, and in vitro cell assays, the research is at an early discovery stage and requires extensive in vivo safety, pharmacokinetic, and efficacy studies before advancing toward clinical development.
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A library of modified VEGFR-2 inhibitors was designed as VEGFR-2 inhibitors. Virtual screening was conducted for the hypothetical library using in silico docking, ADMET, and toxicity studies. Four compounds exhibited high in silico affinity against VEGFR-2 and an acceptable range of the drug-likeness. These compounds were synthesised and subjected to in vitro cytotoxicity assay against two cancer cell lines besides VEGFR-2 inhibitory determination. Compound D-1 showed cytotoxic activity against HCT-116 cells almost double that of sorafenib. Compounds A-1, C-6, and D-1 showed good IC50 values against VEGFR-2. Compound D-1 markedly increased the levels of caspase-8 and BAX expression and decreased the anti-apoptotic Bcl-2 level. Additionally, compound D-1 caused cell cycle arrest at pre-G1 and G2-M phases in HCT-116 cells and induced apoptosis at both early and late apoptotic stages. Compound D-1 decreased the level of TNF-α and IL6 and inhibited TNF-α and IL6. MD simulations studies were performed over 100 ns.
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DOI: 10.1080/14756366.2022.2070744
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