Development of Selective Covalent Janus Kinase 3 Inhibitors
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- 作者：Li Tan ; Koshi Akahane ; Randall McNally ; Kathleen M. S. E. Reyskens ; Scott B. Ficarro ; Suhu Liu ; Grit S. Herter-Sprie ; Shohei Koyama ; Michael J. Pattison ; Katherine Labella ; Liv Johannessen ; Esra A. Akbay ; Kwok-Kin Wong ; David A. Frank ; Jarrod A. Marto ; Thomas A. Look ; J. Simon C. Arthur ; Michael J. Eck ; Nathanael S. Gray
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：August 27, 2015
- 年：2015
- 卷：58
- 期：16
- 页码：6589-6606
- 全文大小：1184K
- ISSN：1520-4804
文摘
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鈥揳ctivity 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 脜 cocrystal 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.