Inhibiting NF-κB-inducing kinase (NIK): Discovery, structure-based design, synthesis, structure–activity relationship, and co-crystal structures

• Published in: Bioorganic & medicinal chemistry letters 2013-03, Vol.23 (5), p.1238-1244
• Main Authors: Li, Kexue, McGee, Lawrence R., Fisher, Ben, Sudom, Athena, Liu, Jinsong, Rubenstein, Steven M., Anwer, Mohmed K., Cushing, Timothy D., Shin, Youngsook, Ayres, Merrill, Lee, Fei, Eksterowicz, John, Faulder, Paul, Waszkowycz, Bohdan, Plotnikova, Olga, Farrelly, Ellyn, Xiao, Shou-Hua, Chen, Guoqing, Wang, Zhulun
• Format: Article
• Language: English
• Subjects: 2-Aminopyrimidine; Alkynes - chemical synthesis; Alkynes - chemistry; Alkynes - pharmacology; Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; Drug Design; HT29 Cells; Humans; Hydrogen Bonding; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Models, Molecular; molecular conformation; NF-kappaB-Inducing Kinase; NIK; Nuclear factor (NF)-κB; p100 processing; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - chemistry; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; structure-activity relationships
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.01.012

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.