| Literature DB >> 28005357 |
Georgette M Castanedo1, Nicole Blaquiere1, Maureen Beresini1, Brandon Bravo1, Hans Brightbill1, Jacob Chen1, Hai-Feng Cui2, Charles Eigenbrot1, Christine Everett1, Jianwen Feng1, Robert Godemann3, Emily Gogol1, Sarah Hymowitz1, Adam Johnson1, Nobuhiko Kayagaki1, Pawan Bir Kohli1, Kathleen Knüppel3, Joachim Kraemer3, Susan Krüger3, Pui Loke4, Paul McEwan4, Christian Montalbetti4, David A Roberts1, Myron Smith4, Stefan Steinbacher5, Swathi Sujatha-Bhaskar1, Ryan Takahashi1, Xiaolu Wang3, Lawren C Wu1, Yamin Zhang2, Steven T Staben1.
Abstract
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).Entities:
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Year: 2017 PMID： 28005357 DOI： 10.1021/acs.jmedchem.6b01363
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446