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Series GSE71695 Query DataSets for GSE71695
Status Public on Oct 31, 2015
Title Characterization of RA839, a non-covalent small-molecule binder to Keap1 and selective activator of Nrf2 signalling
Organism Mus musculus
Experiment type Expression profiling by array
Summary The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors the activity of Nrf2 is inhibited by its interaction with the kelch-like ECH-associated protein 1 (Keap1). Here, we describe RA839, a small molecule that binds non-covalently to the Nrf2-interacting kelch domain of Keap1 with a Kd of approximately 6 µM, as demonstrated by X-ray co-crystallization and isothermal titration calorimetry. Whole-genome DNA arrays showed that at 10 µM RA839 significantly regulated 105 genes in bone marrow-derived macrophages. Canonical pathway mapping of these genes revealed an activation of pathways linked with Nrf2 signalling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knockout macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound CDDO-Me, RA839 prevented the induction of both inducible nitric oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice RA839 acutely induced Nrf2-target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2.
Overall design Gene expression profile of bone marrow derived murine macrophages (BMDM) from Nrf2+/+ or Nrf2-/- mice treated with RA838, siKeap1-1 or siKeap1-2 were compared to untreated DMSO control or siControl. Four biological replicates were used for each sample group.
Contributor(s) Winkel A, Margerie D, Schmoll D
Citation(s) 26459563
Submission date Aug 04, 2015
Last update date Feb 11, 2019
Contact name Daniel Margerie
Organization name Sanofi-Aventis Deutschland GmbH
Department R&D, Digital Data Sciences
Street address Industrial Park Hoechst, Building H831
City Frankfurt am Main
ZIP/Postal code 65926
Country Germany
Platforms (1)
GPL1261 [Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array
Samples (28)
GSM1843251 BMDM_Nrf2+/+_DMSO_Replicate1
GSM1843252 BMDM_Nrf2+/+_DMSO_Replicate2
GSM1843253 BMDM_Nrf2+/+_DMSO_Replicate3
BioProject PRJNA291845

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Supplementary file Size Download File type/resource
GSE71695_RAW.tar 171.4 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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