Menet Christel J, Rompaey Luc Van, Geney Raphaël
Galapagos NV, Generaal de Wittelaan L11A3, Mechelen, Belgium.
Prog Med Chem. 2013;52:153-223. doi: 10.1016/B978-0-444-62652-3.00004-1.
In this review, we describe the current knowledge of the biology of the JAKs. The JAK family comprises the four nonreceptor tyrosine kinases JAK1, JAK2, JAK3, and Tyk2, all key players in the signal transduction from cytokine receptors to transcription factor activation. We also review the progresses made towards the optimization of JAK inhibitors and the importance of their selectivity profile. Indeed, the full array of many medicinal chemistry enabling tools (HTS, X-ray crystallography, scaffold morphing, etc.) has been deployed to successfully design molecules that discriminate among JAK family and other kinases. While the first JAK inhibitor was launched in 2011, this review also summarizes the status of several other small-molecule JAK inhibitors currently in development to treat arthritis, psoriasis, organ rejection, and multiple cancer types.
在本综述中，我们描述了目前关于JAKs生物学的知识。JAK家族由四种非受体酪氨酸激酶JAK1、JAK2、JAK3和Tyk2组成，它们都是从细胞因子受体到转录因子激活的信号转导中的关键参与者。我们还回顾了在JAK抑制剂优化方面取得的进展以及其选择性特征的重要性。实际上，已部署了一系列众多的药物化学支持工具（高通量筛选、X射线晶体学、骨架变形等）来成功设计能够区分JAK家族和其他激酶的分子。虽然首款JAK抑制剂于2011年推出，但本综述也总结了目前正在开发的其他几种用于治疗关节炎、银屑病、器官排斥和多种癌症类型的小分子JAK抑制剂的情况。
