Design, synthesis and biological evaluation of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors bearing a heterocyclic-containing tail as potential anti-tumor agents

被引:2
|
作者
Hao, Shuang [1 ]
Wang, Jia-hui [1 ]
Hou, Liang [1 ]
Liang, Jing-wei [1 ,2 ]
Yan, Jing-han [1 ]
Niu, Yi-fan [1 ]
Li, Xin-yang [1 ,3 ]
Sun, Qi [1 ]
Meng, Fan-hao [1 ]
机构
[1] China Med Univ, Sch Pharm, Shenyang 110122, Peoples R China
[2] Hainan Med Univ, Sch Pharm, Haikou 571199, Peoples R China
[3] China Med Univ, Shengjing Hosp, Dept Pharm, Shenyang 110004, Peoples R China
基金
中国国家自然科学基金;
关键词
Dual-target inhibitors; EGFR; HER-2; Heterocyclic-containing tail approach; Breast cancer; GROWTH-FACTOR RECEPTOR; ACQUIRED-RESISTANCE; EGFR INHIBITORS; LUNG CANCERS; CELL-LINES; IN-VITRO; AMPLIFICATION; MUTATIONS; MECHANISM;
D O I
10.1016/j.bioorg.2024.107686
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A series of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors were designed and synthesized by heterocyclic-containing tail approach. The inhibitory activities against four human epidermal growth factor receptor (HER) isozymes (EGFR, HER-2, HER-3 and HER-4) of all new compounds so designed were investigated in vitro. Compound 12k was found to be the most effective and rather selective dual-target inhibitor of EGFR and HER-2 with inhibitory constant (IC50) values of 6.15 and 9.78 nM, respectively, which was more potent than the clinical used agent Lapatinib (IC50 = 8.41 and 9.41 nM). Meanwhile, almost all compounds showed excellent antiproliferative activities against four cancer cell models (A549, NCI-H1975, SK-BR-3 and MCF-7) and low damage to healthy cells. Among them, compound 12k also exhibited the most prominent antitumor activity. Moreover, the hit compound 12k could bind to EGFR and HER-2 stably in molecular docking and dynamics studies. The following wound healing assay revealed that compound 12k could inhibit the migration of SK-BR-3 cells. Further studies found that compound 12k could arrest cell cycle in the G0/G1 phase and induce SK-BR-3 cells apoptosis. Notably, compound 12k could effectively inhibit breast cancer growth with little toxicity in the SK-BR-3 cell xenograft model. Taken together, in vitro and in vivo results disclosed that compound 12k had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth.
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页数:19
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