Quinazoline derivative compound (11d) as a novel angiogenesis inhibitor inhibiting VEGFR2 and blocking VEGFR2-mediated Akt/mTOR /p70s6k signaling pathway

Abstract

<strong><em>Objective(s): </em></strong>We previously reported a series of quinazoline derivatives as vascular-targeting anticancer agents. In this study, we investigated the mechanism underlying the anti-angiogenic activity of the quinazoline derivative compound <strong>11d</strong>. <strong><em>Materials and Methods: </em></strong>We examined the effects of quinazoline derivative <strong>11d</strong> on vascular endothelial growth factor receptor-2 (VEGFR2) activation via VEGFR2-specific activation assay. Reverse transcription and immunohistochemistry were used to detect vascular endothelial growth factor (VEGF), VEGFR2, and the VEGFR2-mediated Akt/mTOR/p70s6k signaling pathway in human umbilical vascular endothelial cells and hepatocellular carcinoma cells (HepG-2) after treatment with various concentrations of <strong>11d</strong> (0, 6.25, 12.5, and 25 μM) for 24 hr. <strong><em>Results:</em></strong> The compound <strong>11d</strong> exhibited potent inhibitory activity against VEGFR2 with an IC₅₀ of 5.49 μM. This compound significantly downregulated VEGF, VEGFR2, and the VEGFR2-mediated Akt/mTOR/p70s6k signaling pathway <em>in</em> <em>vitro</em>. <strong><em>Conclusion:</em></strong>The mechanism underlying the anti-angiogenic activity of the quinazoline derivative <strong>11d</strong> possibly involves the inhibition of VEGFR2 and the downregulation of VEGF, VEGFR2, and the VEGFR2-mediated Akt/mTOR/p70s6k signaling pathway. Overall, the findings indicate that the studied class of compounds is a source of potential antiproliferative and anti-angiogenic agents, which must be further investigated.