Simpson Graham L, Hughes Jennifer A, Washio Yoshiaki, Bertrand Sophie M
GlaxoSmithKline plc, GSK Medicines Research Centre, Stevenage, Hertfordshire, UK.
Curr Opin Drug Discov Devel. 2009 Sep;12(5):585-96.
The pharmaceutical industry has traditionally targeted the inhibition of dysregulated kinases to treat diseases such as cancer and inflammatory disorders. In contrast to the human genome sequencing project, which aimed to identify novel biological targets, the possibility of activating kinases uses known targets in a novel manner. In an approach that is similar to other target classes (eg, GPCRs and nuclear receptors), transient upregulation of kinase function using small molecules has been increasingly demonstrated to lead to favorable disease outcomes. This review discusses direct small-molecule kinase activators: specifically, how these molecules were discovered, characterized, evaluated and developed into drug leads. The choice of potential targets, the mechanisms of activation and the common strategies used to discover activators are also highlighted.
传统上，制药行业一直致力于通过抑制失调的激酶来治疗癌症和炎症性疾病等。与旨在识别新型生物靶点的人类基因组测序计划不同，以新方式激活已知靶点激酶的可能性备受关注。与其他靶点类别（如GPCR和核受体）类似，越来越多的证据表明，使用小分子短暂上调激酶功能可带来良好的疾病治疗效果。本综述讨论了直接小分子激酶激活剂：具体而言，这些分子是如何被发现、表征、评估并发展成为药物先导物的。文中还重点介绍了潜在靶点的选择、激活机制以及用于发现激活剂的常见策略。
