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<p>The development of novel VEGFR-2 inhibitors remains a promising strategy for targeted breast cancer therapy, particularly against aggressive triple-negative breast cancer subtype. In this study, a series of thiadiazole derivatives were designed, synthesized, and biologically evaluated for their anti-proliferative activity against MDA-MB-231 and MCF-7 breast cancer cell lines. Among them, compound<b> 7</b> exhibited superior cytotoxicity (IC₅₀ = 5.69 µM for MDA-MB-231) and demonstrated remarkable selectivity over normal cell lines. It also displayed potent VEGFR-2 inhibitory activity (IC₅₀ = 0.083 µM), comparable to the reference drug sorafenib (IC₅₀ = 0.1 µM). Mechanistic studies revealed that compound<b> 7</b> induces G2/M phase arrest and promotes late-stage apoptosis, supported by enhanced caspase-3 activation, Bax upregulation, and Bcl-2 suppression. Comprehensive computational analyses—including molecular docking, molecular dynamics (MD) simulations, MM-GBSA binding free energy calculations, ProLIF interaction mapping, and PCA studies—validated the stable and effective binding of compound<b> 7</b> within the ATP-binding pocket of VEGFR-2. Additionally, density functional theory (DFT) calculations supported the compound’s high chemical stability and favorable electronic reactivity. Finally, <i>in silico</i> ADMET and toxicity predictions indicated favorable drug-likeness, low mutagenicity, and a high safety margin. Collectively, these findings position compound<b> 7</b> as a potent and selective VEGFR-2 inhibitor, with promising therapeutic potential in breast cancer management and a strong foundation for further preclinical development.</p>

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Integrated computational and biological evaluations of newly synthesized thiadiazole-based VEGFR-2 inhibitors with targeted anti-breast cancer activity

  • 期刊论文

  • 发表日期：

    2025年7月23日

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  • Bshra A. Alsfouk,
  • Walid E. Elgammal,
  • Hazem Elkady,
  • Hazem A. Mahdy,
  • Dalal Z. Husein,
  • Omar A. Soliman,
  • Abdelrahman A. Abuelkhir,
  • Ibrahim H. Eissa,
  • Eslam B. Elkaeed,
  • Ahmed M. Metwaly

摘要

The development of novel VEGFR-2 inhibitors remains a promising strategy for targeted breast cancer therapy, particularly against aggressive triple-negative breast cancer subtype. In this study, a series of thiadiazole derivatives were designed, synthesized, and biologically evaluated for their anti-proliferative activity against MDA-MB-231 and MCF-7 breast cancer cell lines. Among them, compound 7 exhibited superior cytotoxicity (IC₅₀ = 5.69 µM for MDA-MB-231) and demonstrated remarkable selectivity over normal cell lines. It also displayed potent VEGFR-2 inhibitory activity (IC₅₀ = 0.083 µM), comparable to the reference drug sorafenib (IC₅₀ = 0.1 µM). Mechanistic studies revealed that compound 7 induces G2/M phase arrest and promotes late-stage apoptosis, supported by enhanced caspase-3 activation, Bax upregulation, and Bcl-2 suppression. Comprehensive computational analyses—including molecular docking, molecular dynamics (MD) simulations, MM-GBSA binding free energy calculations, ProLIF interaction mapping, and PCA studies—validated the stable and effective binding of compound 7 within the ATP-binding pocket of VEGFR-2. Additionally, density functional theory (DFT) calculations supported the compound’s high chemical stability and favorable electronic reactivity. Finally, in silico ADMET and toxicity predictions indicated favorable drug-likeness, low mutagenicity, and a high safety margin. Collectively, these findings position compound 7 as a potent and selective VEGFR-2 inhibitor, with promising therapeutic potential in breast cancer management and a strong foundation for further preclinical development.