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发现高强度的甲/烯基 PAD 抑制剂:结构-活性关系,选择性和细胞毒性

Yijiang Jia¹, Sina Bahraminejad², Xin Duan³

¹Medicinal Chemistry Core, Office of Research, University of Tennessee Health Science Center, Memphis, TN, 38163, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.

European journal of medicinal chemistry

|June 6, 2025

概括

研究人员开发了基氨酸脱胺酶 (PADs) 的强有力的抑制剂,这些酶与癌症和自身免疫性疾病有关. 新型纳夫他林和oline化合物显示出强大的抑制与低毒性,提供治疗潜力.

科学领域:

药用化学医学化学
酶学是一种酶学.
药理学药理学是指药理学的学科.

背景情况:

氨基氨酸减小酶 (PADs) 是素化中的关键酶,这种过程与各种疾病有关.
在癌症和自身免疫性疾病中,PAD4和PAD1特别重要,这使得它们成为有吸引力的治疗点.

研究的目的:

设计和合成针对PAD4和PAD1.1的新型,强效抑制剂.
评估这些化合物的抑制活性和结构-活性关系 (SAR).
探索已识别的抑制剂的治疗潜力,用于素化相关疾病.

主要方法:

合成基胺和胺替代化合物.
在体外酶分析以确定对PAD1和PAD4.4的抑制活性 (IC50) .
细胞毒性测定 (CC50) 评估安全性和治疗窗口.
分子对接模拟以调查酶抑制剂相互作用.

主要成果:

与基替代物的纳夫他林和林基支架与Cl-amidine相比,显示出优异的PAD1和PAD4抑制.
强大的抑制剂 (化合物13和16) 达到IC50值低至0.204μM.
化合物13和16具有较低的细胞毒性 (CC50>80μM),这表明治疗窗口很宽.
对接模拟揭示了一种与Glu575在Hydroxy-naphthalene支架上的PAD4上的新型结合相互作用.

结论:

新型基替代纳夫他林和林衍生物是PAD1和PAD4.4的强有力的抑制剂.
这些化合物具有有利的药理动力学特性,包括低细胞毒性和广泛的治疗窗口.
已识别的抑制剂代表了进一步研究PAD酶功能和相关疾病潜在治疗策略的有希望的工具.

关键词:

引定律化引定律化酶抑制可以抑制酶.纳夫他林基脚手架纳夫他林基脚手架这是一种PAD抑制剂.结构与活动的关系.

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