作者
Georgette Castanedo,Nicole Blaquière,Maureen H. Beresini,Brandon Bravo,Hans D. Brightbill,Jacob Chen,Haifeng Cui,Charles Eigenbrot,Christine Everett,Jianwen Feng,Robert Godemann,Emily Gogol,S.G. Hymowitz,Adam R. Johnson,Nobuhiko Kayagaki,Pawan Bir Kohli,Kathleen Knüppel,Joachim Kraemer,Susan Krüger,Pui L. Loke,Paul McEwan,Christian Montalbetti,D. Allen Roberts,M. A. Smith,Stefan Steinbacher,Swathi Sujatha-Bhaskar,Ryan H. Takahashi,Xiaolu Wang,Lawren C. Wu,Yamin Zhang,Steven T. Staben
摘要
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).