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使用定量结构活动关系发现和优化2 (TLK2) 的狭窄频谱抑制剂,使用定量结构活动关系

Christopher R M Asquith¹, Michael P East², Tuomo Laitinen³

¹Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, NC, 27599, USA; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211, Kuopio, Finland; Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

European journal of medicinal chemistry

|April 18, 2024

概括

研究人员开发了针对TLK2激酶的新型氧醇化合物. 这些选择性抑制剂为了解TLK2生物学的化学工具提供了潜在的潜力,解决了以前乱交酶抑制剂的局限性.

科学领域:

药用化学医学化学
化学生物学化学生物学
药物发现药物发现药物发现

背景情况:

氧醇支架是酶药物发现的关键组成部分,一些衍生物被批准作为药物.
在文献中,oxindoles显示了TLK2 (Tousled-like kinase 2) 的持续强大的抑制,作为一种非目标效应.
氧醇可以表现出多种类型的基因组选择性,从狭窄到广谱.

研究的目的:

为了优化TLK2抑制和基于oxindole的化合物的基因组选择性.
开发选择性化学工具化合物,以阐明TLK2的生物学.

主要方法:

定量结构-活动关系 (QSAR) 分析.
酶ATP结合部位的水位映射.
基因组分析和小分子X射线结构分析.
模拟系列的合成.

主要成果:

在特定的文献中确定了一致的TLK2抑制,尽管有不同的基因组形状,但有氧醇.
为增强TLK2抑制和选择性优化化合物.
发现了狭窄光谱,选择性化学工具化合物的子家族,包括128 (UNC-CA2-103).

结论:

新的oxindole类似物显示出作为TLK2.2的选择性抑制剂的潜力.
这些化合物可以作为研究TLK2功能和生物作用的有价值的化学探针.

关键词:

激酶化学工具是一种工具.激酶抑制剂的使用牛津醇是一种氧化物.量化结构与活动关系 (QSAR)类似激酶2 (TLK2) 的托斯莱德.

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