Inhibiting NF-¦ÊB-inducing kinase (NIK): Discovery, structure-based design, synthesis, structure-activity relationship, and co-crystal structures
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- 作者：Kexue Li ; kli@amgen.com ; Lawrence R. McGee ; Ben Fisher ; Athena Sudom ; Jinsong Liu ; Steven M. Rubenstein ; Mohmed K. Anwer ; Timothy D. Cushing ; Youngsook Shin ; Merrill Ayres ; Fei Lee ; John Eksterowicz ; Paul Faulder ; Bohdan Waszkowycz ; Olga Plotnikova ; Ellyn Farrelly ; Shou-Hua Xiao ; Guoqing Chen ; Zhulun Wang
- 关键词：NIK ; Nuclear factor (NF)-¦ÊB ; p100 processing ; 2-Aminopyrimidine
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：1 March, 2013
- 年：2013
- 卷：23
- 期：5
- 页码：1238-1244
- 全文大小：2260 K
文摘
The discovery, structure-based design, synthesis, and optimization of NIK inhibitors are described. Our work began with an HTS hit, imidazopyridinyl pyrimidinamine 1. We utilized homology modeling and conformational analysis to optimize the indole scaffold leading to the discovery of novel and potent conformationally constrained inhibitors such as compounds 25 and 28. Compounds 25 and 31 were co-crystallized with NIK kinase domain to provide structural insights.