发现新型 2,4-二芳基氨基嘧啶腙衍生物,作为能够抑制 FAK 的强效抗甲状腺癌药物。

IF 5.6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Hongting Li, Mei-Qi Jia, Zhao-Long Qin, Changliang Lu, Weili Chu, Ze Zhang, Jinbo Niu, Jian Song, Sai-Yang Zhang, Lijun Fu
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引用次数: 0

摘要

本研究设计、合成了 30 个 2,4-二芳基氨基嘧啶酰肼,并探讨了它们的抗甲状腺癌活性。大多数化合物对FAK过表达的TPC-1细胞具有中等至卓越的细胞毒活性,IC50值在0.113至1.460 μM之间。其中,化合物 14f 对 TPC-1 细胞具有特殊的抗增殖作用(IC50 = 0.113 μM)和强效的 FAK 抑制作用(IC50 = 35 nM)。硅学研究表明,化合物 14f 可以很好地与 FAK(病灶粘附激酶)结合,并具有良好的药代动力学特征。此外,化合物 14f 还能抑制 FAK 在 Tyr397、Tyr576/577 和 Tyr925 处的磷酸化,并且不影响 FAK 在 TPC-1 细胞中的表达水平。化合物 14f 还能有效抑制甲状腺癌细胞 TPC-1 的增殖和迁移。因此,这些新型 4-芳基氨基嘧啶腙衍生物通过抑制 FAK 而表现出了强大的抗甲状腺癌活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Discovery of novel 2,4-diarylaminopyrimidine hydrazone derivatives as potent anti-thyroid cancer agents capable of inhibiting FAK.

In this work, thirty 2,4-diarylaminopyrimidine-based hydrazones were designed, synthesised, and their anti-thyroid cancer activity were explored. The majority of compounds exhibit moderate to excellent cytotoxic activity against FAK overexpressing TPC-1 cells, with IC50 values ranging from 0.113 to 1.460 μM. Among them, compound 14f displayed exceptional anti-proliferative effect against TPC-1 cells (IC50 = 0.113 μM) and potent FAK inhibitory potency (IC50 = 35 nM). In silico studies indicated that compound 14f could well bind to FAK (Focal Adhesion Kinase) and have favourable pharmacokinetic profiles. In addition, compound 14f could inhibit the phosphorylation of FAK at Tyr397, Tyr576/577 and Tyr925, and did not affect the expression level of FAK in TPC-1 cells. Compound 14f was also effective in inhibiting the proliferation and migration of thyroid cancer cells TPC-1. Thus, these novel 4-arylaminopyrimidine hydrazone derivatives exhibited potent anti-thyroid cancer activities through the inhibition of FAK.

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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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