title: Structure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K).
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).
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Georgette M
authors.identifier: 0000-0003-4584-6715
authors.initials: GM
authors.lastname: Castanedo
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Nicole
authors.initials: N
authors.lastname: Blaquiere
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Maureen
authors.initials: M
authors.lastname: Beresini
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Brandon
authors.initials: B
authors.lastname: Bravo
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Hans
authors.initials: H
authors.lastname: Brightbill
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jacob
authors.initials: J
authors.lastname: Chen
authors.affiliation: Pharmaron Beijing Co., Ltd . 6 Taihe Road, BDA, Beijing 100176, P.R. China.
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Cui
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Everett
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Feng
authors.affiliation: Manfred Eigen Campus, Evotec AG , Essener Bogen, 22419 Hamburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Godemann
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Emily
authors.initials: E
authors.lastname: Gogol
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hymowitz
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kayagaki
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Pawan Bir
authors.initials: PB
authors.lastname: Kohli
authors.affiliation: Manfred Eigen Campus, Evotec AG , Essener Bogen, 22419 Hamburg, Germany.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Knüppel
authors.affiliation: Manfred Eigen Campus, Evotec AG , Essener Bogen, 22419 Hamburg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Kraemer
authors.affiliation: Manfred Eigen Campus, Evotec AG , Essener Bogen, 22419 Hamburg, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Krüger
authors.affiliation: Evotec (U.K.) Ltd , 114 Innovation Drive, Milton Park, Abingdon OX14 4Rz, U.K.
authors.forename: Pui
authors.initials: P
authors.lastname: Loke
authors.affiliation: Evotec (U.K.) Ltd , 114 Innovation Drive, Milton Park, Abingdon OX14 4Rz, U.K.
authors.forename: Paul
authors.initials: P
authors.lastname: McEwan
authors.affiliation: Evotec (U.K.) Ltd , 114 Innovation Drive, Milton Park, Abingdon OX14 4Rz, U.K.
authors.forename: Christian
authors.initials: C
authors.lastname: Montalbetti
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Roberts
authors.affiliation: Evotec (U.K.) Ltd , 114 Innovation Drive, Milton Park, Abingdon OX14 4Rz, U.K.
authors.forename: Myron
authors.initials: M
authors.lastname: Smith
authors.affiliation: Proteros Biostructures GmbH , Bunsenstrasse 7a, D-82152 Martinsried, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Steinbacher
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Swathi
authors.initials: S
authors.lastname: Sujatha-Bhaskar
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Manfred Eigen Campus, Evotec AG , Essener Bogen, 22419 Hamburg, Germany.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Lawren C
authors.initials: LC
authors.lastname: Wu
authors.affiliation: Pharmaron Beijing Co., Ltd . 6 Taihe Road, BDA, Beijing 100176, P.R. China.
authors.forename: Yamin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Staben
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D004285:Dogs; D057809:HEK293 Cells; D006367:HeLa Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006572:Heterocyclic Compounds, Bridged-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D010077:Oxazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D006572:Heterocyclic Compounds, Bridged-Ring; D007093:Imidazoles; D007555:Isoxazoles; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D010077:Oxazepines; D010080:Oxazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C000620971:10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl)-N3-methyl-5,6-dihydroimidazo(1,2-d)(1,4)benzoxazepine-2,3-dicarboxamide; C000620970:10-fluoro-9-(3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl)-2,5-diazatetracyclo(11.1.1.0(2,6).0(7,12))pentadeca-3,5,7(12),8,10-pentaene-4-carboxamide; C582924:2-(3-(2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide