Development of Selective Covalent Janus Kinase 3 Inhibitors.
Development of Selective Covalent Janus Kinase 3 Inhibitors.
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DOI：
10.1021/acs.jmedchem.5b00710
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发表时间：
2015-08-27
影响因子：
7.3
通讯作者：
Gray NS
中科院分区：
文献类型：
--
作者：
Tan L;Akahane K;McNally R;Reyskens KM;Ficarro SB;Liu S;Herter-Sprie GS;Koyama S;Pattison MJ;Labella K;Johannessen L;Akbay EA;Wong KK;Frank DA;Marto JA;Look TA;Arthur JS;Eck MJ;Gray NS
Janus激酶(JAKs)及其下游效应因子信号转导和转录激活蛋白(STATs)构成免疫细胞信号通路，在先天免疫、炎症和造血中起重要作用，免疫疾病和癌症中常可观察到调节失调。JAK ATP结合口袋的高度结构保守性给寻求开发高选择性抑制剂作为药理探针和临床药物的药物化学家提出了相当大的挑战。在这里，我们报道了利用JAK3中独特的半胱氨酸(Cys909)残基的2，4-取代嘧啶作为共价JAK3抑制剂的发现和优化。利用生化和转化的BA/F3细胞分析对结构-活性-关系(SAR)进行研究，鉴定出有效和选择性的抑制剂，如化合物9和45。JAK3与9形成的2.9？共晶结构证实了共价相互作用。化合物9具有良好的药代动力学性质，适合在体内使用。这些抑制剂提供了一套有用的工具来药理学地询问JAK3依赖的生物学。
The Janus Kinases (JAKs) and their downstream effectors Signal Transducer and Activator of Transcription proteins (STATs) form a critical immune cell signaling circuit, which is of fundamental importance in innate immunity, inflammation and hematopoiesis and dysregulation is frequently observed in immune disease and cancer. The high degree of structural conservation of the JAK ATP binding pockets has posed a considerable challenge to medicinal chemists seeking to develop highly selective inhibitors as pharmacological probes and as clinical drugs. Here we report the discovery and optimization of 2,4-substituted pyrimidines as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of structure-activity-relationship (SAR) utilizing biochemical and transformed Ba/F3 cellular assays resulted in identification of potent and selective inhibitors such as compounds 9 and 45. A 2.9 Å co-crystal structure of JAK3 in complex with 9 confirms the covalent interaction. Compound 9 exhibited decent pharmacokinetic properties and is suitable for use in vivo. These inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology.