Design and Analysis of the 4-Anilinoquin(az)oline Kinase Inhibition Profiles of GAK/SLK/STK10 Using Quantitative Structure-Activity Relationships.,ChemMedChem

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Design and Analysis of the 4-Anilinoquin(az)oline Kinase Inhibition Profiles of GAK/SLK/STK10 Using Quantitative Structure-Activity Relationships.
ChemMedChem ( IF 3.6 ) Pub Date : 2019-11-01 , DOI: 10.1002/cmdc.201900521
Christopher R M Asquith _{1,

2} , Tuomo Laitinen ₃ , James M Bennett ₄ , Carrow I Wells ₂ , Jonathan M Elkins _{4,

5} , William J Zuercher _{2,

6} , Graham J Tizzard ₇ , Antti Poso _{3,

8}

Affiliation

The 4-anilinoquinoline and 4-anilinoquinazoline ring systems have been the focus of significant efforts in prior kinase drug discovery programs, which have led to approved medicines. Broad kinome profiles of these compounds have now been assessed with the advent of advanced screening technologies. These ring systems, while originally designed for specific targets including epidermal growth factor receptor (EGFR), but actually display a number of potent collateral kinase targets, some of which have been associated with negative clinical outcomes. We have designed and synthesized a series of 4-anilinoquin(az)olines in order to better understand the structure-activity relationships of three main collateral kinase targets of quin(az)oline-based kinase inhibitors: cyclin G associated kinase (GAK), STE20-like serine/threonine-protein kinase (SLK) and serine/threonine-protein kinase 10 (STK10). This was achieved through a series of quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites and extensive small-molecule X-ray structural analysis.

中文翻译：

利用定量结构-活性关系设计和分析GAK / SLK / STK10的4-苯胺基喹啉（az）oline激酶抑制谱。

4-苯胺基喹啉和4-苯胺基喹唑啉环系统一直是现有激酶药物发现计划中的重大工作重点，这些计划已开发出获批的药物。随着先进的筛选技术的出现，现在已经评估了这些化合物的广泛的动力学特征。这些环系统最初是为包括表皮生长因子受体（EGFR）在内的特定靶标设计的，但实际上显示了许多有效的附带激酶靶标，其中一些与阴性临床结局有关。我们设计和合成了一系列4-苯胺基喹啉（az）脯氨酸，以便更好地了解基于喹（唑啉的激酶抑制剂的三个主要附带激酶靶的结构-活性关系：细胞周期蛋白G相关激酶（GAK），STE20样丝氨酸/苏氨酸蛋白激酶（SLK）和丝氨酸/苏氨酸蛋白激酶10（STK10）。这是通过一系列定量构效关系（QSAR）分析，激酶ATP结合位点的水位分析以及广泛的小分子X射线结构分析实现的。

更新日期：2019-11-27

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