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

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Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States
Pharmaron Beijing Co., Ltd. 6 Taihe Road, BDA, Beijing 100176, P.R. China
§ Manfred Eigen Campus, Evotec AG, Essener Bogen, 22419 Hamburg, Germany
Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4Rz, U.K.
Proteros Biostructures GmbH, Bunsenstrasse 7a, D-82152 Martinsried, Germany
*For G.C. phone, (650)225-1538; E-mail, [email protected]
*For S.T.S.: phone, (650)467-3103; E-mail, [email protected]
Cite this: J. Med. Chem. 2017, 60, 2, 627–640
Publication Date (Web):December 22, 2016
Copyright © 2016 American Chemical Society

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    Abstract Image

    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).

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b01363.

    • Additional synthetic procedures, biochemical and cellular assay condtions and crystallography details (PDF)

    • Molecular formula strings (CSV)

    Accession Codes

    PDB codes have been assigned as follows: 5T8F for PI3Kδ with taselisib, 5T8Q for NIK with Frag17, 5T8P for NIK with compound 2, 5T8O for NIK with compound 3. Atomic coordinates and experimental data will be released upon publication.

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