Abstract：
The oxindole scaffold has been the center of several kinase drug discovery programs, some of which have led to approved medicines. A series of two oxindole matched pairs from the literature were identified where TLK2 was potently inhibited as an off-target kinase. The oxindole has long been considered a promiscuous kinase inhibitor template, but across these four specific literature oxindoles TLK2 activity was consistent, while the kinome profile was radically different ranging from narrow to broad spectrum kinome coverage. We synthesized a large series of analogues, utilizing quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites, kinome profiling, and small-molecule x-ray structural analysis to optimize TLK2 inhibition and kinome selectivity. This resulted in the identification of several narrow spectrum, sub-family selective, chemical tool compounds including 128 (UNC-CA2-103) that could enable elucidation of TLK2 biology.
摘要：
羟吲哚支架一直是几个激酶药物发现计划的中心，其中一些导致批准的药物。鉴定了来自文献的一系列两个羟吲哚匹配对,其中TLK2被有效抑制为脱靶激酶。羟吲哚一直被认为是混杂的激酶抑制剂模板，但是在这四个特定的文献中，oxindolesTLK2的活性是一致的，而从窄谱到广谱的kinome覆盖则截然不同。我们合成了大量的类似物,利用定量结构-活性关系(QSAR)分析，激酶ATP结合位点的水图，Kinome剖析,和小分子X射线结构分析以优化TLK2抑制和激酶选择性。这导致了几个窄光谱的鉴定，亚家族选择性，化学工具化合物，包括128（UNC-CA2-103），可以阐明TLK2生物学。
