Discovery of N-(1,3,4-thiadiazol-2-yl)benzamide derivatives containing a 6,7-methoxyquinoline structure as novel EGFR/HER-2 dual-target inhibitors against cancer growth and angiogenesis.

Autor: Li XY; Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang 110004, PR China; School of Pharmacy, China Medical University, Shenyang 110122, PR China., Wang DP; Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang 110004, PR China; School of Pharmacy, China Medical University, Shenyang 110122, PR China., Li S; Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang 110004, PR China; School of Pharmacy, China Medical University, Shenyang 110122, PR China., Xue WH; School of Pharmacy, China Medical University, Shenyang 110122, PR China., Qian XH; School of Pharmacy, China Medical University, Shenyang 110122, PR China., Liu KL; School of Pharmacy, China Medical University, Shenyang 110122, PR China., Li YH; School of Pharmacy, China Medical University, Shenyang 110122, PR China., Lin QQ; School of Pharmacy, China Medical University, Shenyang 110122, PR China., Dong G; School of Pharmacy, China Medical University, Shenyang 110122, PR China., Meng FH; School of Pharmacy, China Medical University, Shenyang 110122, PR China., Jian LY; Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang 110004, PR China. Electronic address: jianly@sj-hospital.org.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2022 Feb; Vol. 119, pp. 105469. Date of Electronic Publication: 2021 Nov 06.
DOI: 10.1016/j.bioorg.2021.105469
Abstrakt: Targeting EGFR and HER-2 is an essential direction for cancer treatment. Here, a series of N-(1,3,4-thiadiazol-2-yl)benzamide derivatives containing a 6,7-methoxyquinoline structure was designed and synthesized to serve as EGFR/HER-2 dual-target inhibitors. The kinase assays verified that target compounds could inhibit the kinase activity of EGFR and HER-2 selectively. The results of CCK-8 and 3D cell viability assays confirmed that target compounds had excellent anti-proliferation ability against breast cancer cells (MCF-7 and SK-BR-3) and lung cancer cells (A549 and H1975), particularly against SK-BR-3 cells, while the inhibitory effect on healthy breast cells (MCF-10A) and lung cells (Beas-2B) was weak. Among them, the hit compound YH-9 binded to EGFR and HER-2 stably in molecular dynamics studies. Further studies found thatYH-9could induce the release of cytochrome c and inhibit proliferation by promoting ROS expression in SK-BR-3 cells. Moreover,YH-9could diminish the secretion of VEGF and bFGF factors in SK-BR-3 cells, then inhibited tube formation and angiogenesis. Notably,YH-9could effectively inhibit breast cancer growth and angiogenesis with little toxicity in the SK-BR-3 cell xenograft model. Taken together,in vitroandin vivoresults revealed that YH-9 had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth and angiogenesis.
(Copyright © 2021. Published by Elsevier Inc.)
Databáze: MEDLINE
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