Oncogenic activation of receptor tyrosine kinases (RTKs) such as MET is associated with cancer initiation and progression. We designed and synthesized a new series of quinazoline derivatives bearing 1,2,3-triazole moiety as targeted anticancer agents. The MET inhibitory effect of synthesized compounds was assessed by homogeneous time-resolved fluorescence (HTRF) assay and western blot analysis. Sulforhodamine B assay was conducted to examine the antiproliferative effects of synthetic compounds against 6 cancer cell lines from different origins including MET-dependent AsPC-1, EBC-1 and MKN-45 cells and also Mia-Paca-2, HT-29 and K562 cells. The growth inhibitory effect of compounds in a three-dimensional spheroid culture was examined by acid phosphatase (APH) assay, while apoptosis induction was evaluated by Annexin V/propidium iodide method. Compound 8c bearing p-methyl benzyl moiety on the triazole ring exhibited the highest MET inhibitory capacity among tested agents that was further confirmed by western blot findings. Derivatives 8c and 8h exhibited considerable antiproliferative effects against all tested cell lines, with more inhibitory effects against MET-positive cells with IC₅₀ values as low as 6.1 μM. These two agents also significantly suppressed cell growth in spheroid cultures and induced apoptosis in MET overexpressing AsPC-1 cells. Moreover, among a panel of 24 major oncogenic kinases, the PDGFRA kinase was identified as a target of 8c and 8h compounds. The docking study results of compounds 8c and 8h were in agreement with experimental findings. The results of the present study suggest that quinazoline derivatives bearing 1,2,3-triazole moiety may represent promising targeted anticancer agents.

受体酪氨酸激酶 (RTK)（例如 MET）的致癌激活与癌症的发生和进展相关。我们设计并合成了一系列新的带有1,2,3-三唑部分的喹唑啉衍生物作为靶向抗癌药物。通过均相时间分辨荧光（HTRF）测定和蛋白质印迹分析评估合成化合物的 MET 抑制效果。进行磺胺罗丹明 B 测定以检查合成化合物对来自不同来源的 6 种癌细胞系的抗增殖作用，包括 MET 依赖性 AsPC-1、EBC-1 和 MKN-45 细胞以及 Mia-Paca-2、HT-29 和 K562细胞。通过酸性磷酸酶（APH）测定检测化合物在三维球体培养物中的生长抑制作用，并通过膜联蛋白V/碘化丙啶法评估细胞凋亡诱导作用。在三唑环上带有对甲基苄基部分的化合物8c在测试的药物中表现出最高的MET抑制能力，这通过蛋白质印迹结果得到进一步证实。衍生物8c和8h对所有测试的细胞系均表现出相当大的抗增殖作用，对MET阳性细胞具有更强的抑制作用，IC ₅₀值低至6.1 μM。这两种药物还显着抑制球状培养物中的细胞生长，并诱导 MET 过表达 AsPC-1 细胞的细胞凋亡。此外，在一组 24 种主要致癌激酶中，PDGFRA 激酶被确定为8c和8h化合物的靶标。化合物8c和8h的对接研究结果与实验结果一致。本研究的结果表明带有1,2,3-三唑部分的喹唑啉衍生物可能代表有前途的靶向抗癌药物。