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


METHODS
We examined the effects of quinazoline derivative 11d: 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 11d: (0, 6.25, 12.5, and 25 μM) for 24 hr.


RESULTS
The compound 11d: 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 in vitro.


CONCLUSIONS
The mechanism underlying the anti-angiogenic activity of the quinazoline derivative 11d: 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.
Department of Pharmacy, Anhui Medical University, Hefei 230032, China.
Zeng
Z
Li
Department of Pharmacy, Xiangnan University, Chenzhou 423000, China.
Bin
B
Wang
Department of Chirurgery, First Affiliated Hospital of Anhui Medical University, Hefei 230032, China.
Liang
L
Tang
Department of Pharmacy, Anhui Medical University, Hefei 230032, China; Department of Chirurgery, First Affiliated Hospital of Anhui Medical University, Hefei 230032, China.
Shuangsheng
S
Chen
Department of Pharmacy, Anhui Medical University, Hefei 230032, China.
Jun
J
Li
Quinazoline derivatives; VEGF; VEGFR2; anti-angiogenic Akt/mTOR/p70s6k mechanism