Design and Analysis of the 4-Anilinoquin(az)oline Kinase Inhibition Profiles of GAK/SLK/STK10 Using Quantitative Structure-Activity Relationships
Design and Analysis of the 4-Anilinoquin(az)oline Kinase Inhibition Profiles of GAK/SLK/STK10 Using Quantitative Structure-Activity Relationships
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DOI：
10.1002/cmdc.201900521
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发表时间：
2019-11-26
期刊：
影响因子：
3.4
通讯作者：
Poso, Antti
中科院分区：
文献类型：
--
作者：
Asquith, Christopher R. M.;Laitinen, Tuomo;Poso, Antti
4-苯胺基喹啉和4-苯胺基喹唑啉环系统已经成为先前激酶药物发现计划中的重大努力的焦点，这导致了批准的药物。随着先进筛选技术的出现，现已对这些化合物的广泛激酶组谱进行了评估。这些环系统虽然最初是针对包括表皮生长因子受体（EGFR）在内的特定靶点设计的，但实际上显示出许多有效的附带激酶靶点，其中一些与阴性临床结果相关。我们设计并合成了一系列4-苯胺基喹啉类化合物，以更好地了解喹啉类激酶抑制剂的三个主要旁路激酶靶点：细胞周期蛋白G相关激酶（GAK）、STE 20样丝氨酸/苏氨酸蛋白激酶（SLK）和丝氨酸/苏氨酸蛋白激酶10（STK 10）的构效关系。这是通过一系列的定量构效关系（QSAR）分析，水映射的激酶ATP结合位点和广泛的小分子X-射线结构分析。
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.