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J Med Chem. 2017 Jan 26;60(2):627-640. doi: 10.1021/acs.jmedchem.6b01363. Epub 2017 Jan 12.

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

Author information

1
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
2
Pharmaron Beijing Co., Ltd . 6 Taihe Road, BDA, Beijing 100176, P.R. China.
3
Manfred Eigen Campus, Evotec AG , Essener Bogen, 22419 Hamburg, Germany.
4
Evotec (U.K.) Ltd , 114 Innovation Drive, Milton Park, Abingdon OX14 4Rz, U.K.
5
Proteros Biostructures GmbH , Bunsenstrasse 7a, D-82152 Martinsried, Germany.

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).

PMID:
28005357
DOI:
10.1021/acs.jmedchem.6b01363
[Indexed for MEDLINE]

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