Henderson Scott H, Sorrell Fiona, Bennett James, Hanley Marcus T, Robinson Sean, Hopkins Navratilova Iva, Elkins Jonathan M, Ward Simon E
Sussex Drug Discovery Centre, University of Sussex, Brighton BN1 9RH, U.K.
Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, U.K.
ACS Med Chem Lett. 2020 Jun 30;11(8):1620-1626. doi: 10.1021/acsmedchemlett.0c00279. eCollection 2020 Aug 13.
Kinases represent one of the most intensively pursued groups of targets in modern-day drug discovery. Often it is desirable to achieve selective inhibition of the kinase of interest over the remaining ∼500 kinases in the human kinome. This is especially true when inhibitors are intended to be used to study the biology of the target of interest. We present a pipeline of open-source software that analyzes public domain data to repurpose compounds that have been used in previous kinase inhibitor development projects. We define the dual-specificity tyrosine-regulated kinase 1A (DYRK1A) as the kinase of interest, and by addition of a single methyl group to the chosen starting point we remove glycogen synthase kinase β (GSK3β) and cyclin-dependent kinase (CDK) inhibition. Thus, in an efficient manner we repurpose a GSK3β/CDK chemotype to deliver , a highly selective DYRK1A inhibitor.
激酶是现代药物研发中研究最为深入的靶点类别之一。通常，人们希望能够选择性抑制目标激酶，而不是人类激酶组中其余约500种激酶。当抑制剂旨在用于研究目标激酶的生物学特性时，情况尤其如此。我们展示了一个开源软件流程，该流程分析公共领域数据，以重新利用先前激酶抑制剂开发项目中使用过的化合物。我们将双特异性酪氨酸调节激酶1A（DYRK1A）定义为目标激酶，并通过在选定的起始点添加一个甲基，消除了糖原合酶激酶β（GSK3β）和细胞周期蛋白依赖性激酶（CDK）的抑制作用。因此，我们以一种高效的方式将GSK3β/CDK化学类型重新用于开发一种高度选择性的DYRK1A抑制剂。
