Thiadiazole-Derived VEGFR-2 Inhibitors: From Design to Anticancer Evaluation.

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Computational Chemistry

Background:

• Angiogenesis, driven by VEGFR-2, is crucial for tumor growth and metastasis.
• Targeting VEGFR-2 is a validated strategy for anti-cancer drug development.
• Novel small molecules are needed to overcome resistance and improve efficacy.

Purpose of the Study:

• To design, synthesize, and evaluate novel thiadiazole derivatives as potential VEGFR-2 inhibitors.
• To assess the antiangiogenic and anticancer effects of these compounds.
• To elucidate the mechanism of action of the most potent derivative.

Main Methods:

• Pharmacophore-guided design and synthesis of thiadiazole derivatives.
• In vitro enzymatic assays for VEGFR-2 inhibition.
• In vitro cytotoxicity assays against cancer cell lines (MCF-7) and normal cells (WI-38).
• Flow cytometry for cell cycle analysis and apoptosis detection.
• Molecular docking, molecular dynamics simulations, and free energy calculations.

Main Results:

• Compound 9b exhibited potent VEGFR-2 inhibition (IC50 = 0.030 ± 0.001 μM), surpassing Sorafenib.
• Compound 9b showed high cytotoxicity against MCF-7 cells (IC50 = 8.06 ± 0.7 μM) with minimal toxicity to WI-38 cells.
• Compound 9b induced G2/M cell cycle arrest and apoptosis, evidenced by altered expression of apoptosis-related proteins (Bax, Bcl-2, caspase-3).
• In silico studies confirmed stable binding of compound 9b to the VEGFR-2 active site.

Conclusions:

• Compound 9b is a potent VEGFR-2 inhibitor with significant antiangiogenic and anticancer properties.
• The compound induces cancer cell death via apoptosis and cell cycle arrest.
• Combined experimental and computational data validate compound 9b as a promising therapeutic candidate for VEGFR-2-targeted cancer therapy.