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通过调节表皮生长因子受体酪氨酸激酶探讨选定的 1,3,5-三嗪类化合物的抗乳腺癌活性。

Anti‑breast cancer activity of selected 1,3,5‑triazines via modulation of EGFR‑TK.

机构信息

State Key Lab of Mechanical System and Vibration, Robotics Institute, Shanghai Jiao Tong University, Shanghai 200240, P.R. China.

Comprehensive Breast Health Center, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.

出版信息

Mol Med Rep. 2018 Nov;18(5):4175-4184. doi: 10.3892/mmr.2018.9426. Epub 2018 Aug 24.

Abstract

The present study investigated the effect of certain 1,3,5‑triazine derivatives on epidermal growth factor receptor‑tyrosine kinase (EGFR‑TK). The results suggested that 1,3,5‑triazine derivatives exhibited optimal drug likeness via molinspiration and proved to be effective drug candidates as potential anticancer agents. The molecules were demonstrated to interact with key catalytic residues of EGFR, including Asn818, Lys721, Leu694, Val702 and Met742 as demonstrated in molecular docking experiments. Compound 1d was demonstrated to be the most potent analogue with an inhibitory constant of 0.44 nM, against EGFR‑TK in in‑vitro enzyme inhibition assay. Compound 1d was further evaluated for its effect on the cellular viability of three breast cancer cell lines, including highly metastatic MDAMB231, human epidermal growth factor receptor 2‑positive BT474 and estrogen receptorpositive MCF7 cells, using an MTT assay and apoptosis analysis. Western blot analysis was performed to examine the levels of β‑catenin in the control and treated cells. Based on the findings of the current study, the chemical 1,3,5‑triazine series are potential novel inhibitors of EGFR‑TK and β‑catenin signaling, and may be potent anti‑breast cancer agents.

摘要

本研究探讨了某些 1,3,5-三嗪衍生物对表皮生长因子受体酪氨酸激酶(EGFR-TK)的影响。结果表明,1,3,5-三嗪衍生物通过 molinspiration 显示出最佳的药物相似性,并被证明是有效的候选药物,作为潜在的抗癌药物。分子对接实验表明,这些分子与 EGFR 的关键催化残基相互作用,包括 Asn818、Lys721、Leu694、Val702 和 Met742。在体外酶抑制试验中,化合物 1d 被证明是最有效的类似物,其对 EGFR-TK 的抑制常数为 0.44 nM。化合物 1d 进一步通过 MTT 分析和凋亡分析,评估了其对三种乳腺癌细胞系(包括高转移性 MDAMB231、人表皮生长因子受体 2 阳性 BT474 和雌激素受体阳性 MCF7 细胞)的细胞活力的影响。Western blot 分析用于检测对照和处理细胞中 β-连环蛋白的水平。基于本研究的结果,1,3,5-三嗪系列化合物是潜在的新型 EGFR-TK 和 β-连环蛋白信号通路抑制剂,可能是有效的抗乳腺癌药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b92b/6172377/ca77ed320e0d/MMR-18-05-4175-g00.jpg

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