Quinazoline derivative compound (۱۱d) as a novel angiogenesis inhibitor inhibiting VEGFR۲ and blocking VEGFR۲-mediated Akt/mTOR /p۷۰s۶k signaling pathway

Objective(s): 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 ۱۱d. Materials and Methods: We examined the effects of quinazoline derivative ۱۱d on vascular endothelial growth factor receptor-۲ (VEGFR۲) activation via VEGFR۲-specific activation assay. Reverse transcription and immunohistochemistry were used to detect vascular endothelial growth factor (VEGF), VEGFR۲, and the VEGFR۲-mediated Akt/mTOR/p۷۰s۶k signaling pathway in human umbilical vascular endothelial cells and hepatocellular carcinoma cells (HepG-۲) after treatment with various concentrations of ۱۱d (۰, ۶.۲۵, ۱۲.۵, and ۲۵ μM) for ۲۴ hr. Results: The compound ۱۱d exhibited potent inhibitory activity against VEGFR۲ with an IC۵۰ of ۵.۴۹ μM. This compound significantly downregulated VEGF, VEGFR۲, and the VEGFR۲-mediated Akt/mTOR/p۷۰s۶k signaling pathway in vitro. Conclusion:The mechanism underlying the anti-angiogenic activity of the quinazoline derivative ۱۱d possibly involves the inhibition of VEGFR۲ and the downregulation of VEGF, VEGFR۲, and the VEGFR۲-mediated Akt/mTOR/p۷۰s۶k 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.

Keywords:

anti-angiogenic Akt/mTOR/p۷۰s۶k mechanism , Quinazoline derivatives , VEGF , VEGFR۲