Structure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K)

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• 作者：Georgette M. CastanedoNicole Blaquiere ; Maureen Beresini ; Brandon Bravo ; Hans Brightbill ; Jacob Chen ; Hai-Feng Cui ; Charles Eigenbrot ; Christine Everett ; Jianwen Feng ; Robert Godemann ; Emily Gogol ; Sarah Hymowitz ; Adam Johnson ; Nobuhiko Kayagaki ; Pawan Bir Kohli ; Kathleen Knüppel ; Joachim Kraemer ; Susan Krüger ; Pui Loke ; Paul McEwan ; Christian Montalbetti ; David A. Roberts ; Myron Smith ; Stefan Steinbacher ; Swathi Sujatha-Bhaskar ; Ryan Takahashi ; Xiaolu Wang ; Lawren C. Wu ; Yamin Zhang ; Steven T. Staben
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：January 26, 2017
• 年：2017
• 卷：60
• 期：2
• 页码：627-640
• 全文大小：779K
• ISSN：1520-4804

文摘

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).