作为新型表皮生长因子受体抑制剂的 3-氨基吡嗪-2-甲酰胺衍生物的设计、合成和生物学评价。

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-11-05 eCollection Date: 2024-11-14 DOI:10.1021/acsmedchemlett.4c00431

Jia Zheng, Wei Zhang, Dan Ni, Shuang Zhao, Yi He, Junchi Hu, Linfeng Li, Yongjun Dang, Zufeng Guo, Shenyou Nie

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引用次数: 0

摘要

表皮生长因子受体（FGFR）一直被认为是一种关键的致癌驱动因子和有希望的癌症治疗靶点。在此，我们报告了作为新型 FGFR 抑制剂的 3-氨基-N-（3,5-二羟基苯基）-6-甲基吡嗪-2-甲酰胺衍生物的设计与合成。通过 SAR 探索，发现 18i 是一种泛 FGFR 抑制剂，对 FGFR1-4 具有良好的体外活性。此外，18i 还能在亚摩尔水平上阻断 FGFR 和下游信号通路的激活，并在多种 FGFR 异常的癌细胞系中显示出强大的抗肿瘤活性。为了研究 18i 在 FGFR2 结合位点内的可能结合模式，进行了分子对接。这些结果表明，化合物 18i 是一种很有希望用于进一步药物开发的候选化合物。

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Design, Synthesis, and Biological Evaluation of 3-Amino-pyrazine-2-carboxamide Derivatives as Novel FGFR Inhibitors.

FGFR has been considered a crucial oncogenic driver and promising target for cancer therapy. Herein, we reported the design and synthesis of 3-amino-N-(3,5-dihydroxyphenyl)-6-methylpyrazine-2-carboxamide derivatives as novel FGFR inhibitors. SAR exploration led to the identification of 18i as a pan-FGFR inhibitor with favorable in vitro activity against FGFR1-4. Moreover, 18i blocked the activation of FGFR and downstream signaling pathways at the submicromolar level and exhibited potent antitumor activity in multiple cancer cell lines with FGFR abnormalities. Molecular docking was performed to investigate the possible binding modes of 18i within the binding site of FGFR2. These results suggest that compound 18i is a promising candidate for further drug discovery.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.

期刊最新文献

Issue Editorial Masthead Issue Publication Information In This Issue, Volume 15, Issue 11 Design, Synthesis, and Biological Evaluation of 3-Amino-pyrazine-2-carboxamide Derivatives as Novel FGFR Inhibitors Design, Synthesis, and Biological Evaluation of 3-Amino-pyrazine-2-carboxamide Derivatives as Novel FGFR Inhibitors.