Structure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K).
Georgette M CastanedoNicole BlaquiereMaureen BeresiniBrandon BravoHans BrightbillJacob ChenHai-Feng CuiCharles EigenbrotChristine EverettJianwen FengRobert GodemannEmily GogolSarah HymowitzAdam JohnsonNobuhiko KayagakiPawan Bir KohliKathleen KnüppelJoachim KraemerSusan KrügerPui LokePaul McEwanChristian MontalbettiDavid A RobertsMyron SmithStefan SteinbacherSwathi Sujatha-BhaskarRyan TakahashiXiaolu WangLawren C WuYamin ZhangSteven T StabenPublished in: Journal of medicinal chemistry (2017)
We report here structure-guided optimization of a novel series of NF-κB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-κB2 (p52/REL-B) but not canonical NF-κB1 (REL-A/p50).