采用含杂环尾部方法设计合成了一系列新型喹唑啉衍生的EGFR/HER-2双靶点抑制剂。体外研究了如此设计的所有新化合物对四种人表皮生长因子受体（HER）同工酶（EGFR、HER-2、HER-3和HER-4）的抑制活性。化合物12k被发现是EGFR和HER-2最有效、最具选择性的双靶点抑制剂，抑制常数（IC50）值分别为6.15和9.78 nM，比临床使用的药物拉帕替尼（IC50= 8.41 和 9.41 nM）。同时，几乎所有化合物都对四种癌细胞模型（A549、NCI-H1975、SK-BR-3和MCF-7）表现出优异的抗增殖活性，并且对健康细胞的损害较低。其中，化合物12k也表现出最突出的抗肿瘤活性。此外，在分子对接和动力学研究中，命中化合物12k可以与EGFR和HER-2稳定结合。以下伤口愈合测定表明，化合物12k可以抑制SK-BR-3细胞的迁移。进一步研究发现，化合物12k可以将细胞周期阻滞在G0/G1期，并诱导SK-BR-3细胞凋亡。值得注意的是，化合物 12k 在 SK-BR-3 细胞异种移植模型中可以有效抑制乳腺癌生长，且毒性很小。综上所述，体外和体内结果表明，化合物 12k 作为 EGFR/HER-2 双靶点抑制剂具有抑制乳腺癌生长的高药物潜力。版权所有 © 2024 Elsevier Inc. 保留所有权利。

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.Copyright © 2024 Elsevier Inc. All rights reserved.