title: Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism.
abstract: Keap1 binds to the Nrf2 transcription factor to promote its degradation, resulting in the loss of gene products that protect against oxidative stress. While cell-active small molecules have been identified that modify cysteines in Keap1 and effect the Nrf2 dependent pathway, few act through a non-covalent mechanism. We have identified and characterized several small molecule compounds that specifically bind to the Keap1 Kelch-DC domain as measured by NMR, native mass spectrometry and X-ray crystallography. One compound upregulates Nrf2 response genes measured by a luciferase cell reporter assay. The non-covalent inhibition strategy presents a reasonable course of action to avoid toxic side-effects due to non-specific cysteine modification.
authors: Biogen Idec, Drug Discovery, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors: Douglas
authors: D
authors: Marcotte
authors: Weike
authors: W
authors: Zeng
authors: Jean-Christophe
authors: JC
authors: Hus
authors: Andres
authors: A
authors: McKenzie
authors: Cathy
authors: C
authors: Hession
authors: Ping
authors: P
authors: Jin
authors: Chris
authors: C
authors: Bergeron
authors: Alexey
authors: A
authors: Lugovskoy
authors: Istvan
authors: I
authors: Enyedy
authors: Hernan
authors: H
authors: Cuervo
authors: Deping
authors: D
authors: Wang
authors: Cédric
authors: C
authors: Atmanene
authors: Dominique
authors: D
authors: Roecklin
authors: Malgorzata
authors: M
authors: Vecchi
authors: Valérie
authors: V
authors: Vivat
authors: Joachim
authors: J
authors: Kraemer
authors: Dirk
authors: D
authors: Winkler
authors: Victor
authors: V
authors: Hong
authors: Jianhua
authors: J
authors: Chao
authors: Matvey
authors: M
authors: Lukashev
authors: Laura
authors: L
authors: Silvian
mesh_terms: D002352:Carrier Proteins; D018360:Crystallography, X-Ray; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; C521116:KLHDC1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D054852:Small Molecule Libraries