Discovery and characterization of novel peptide inhibitors of the NRF2/MAFG/DNA ternary complex for the treatment of cancer.
Antioxidant Response Elements
/ drug effects
DNA
/ chemistry
Drug Design
Drug Stability
Electrophoretic Mobility Shift Assay
Half-Life
HeLa Cells
Humans
MafG Transcription Factor
/ antagonists & inhibitors
NF-E2-Related Factor 2
/ antagonists & inhibitors
Neoplasms
/ drug therapy
Peptides
/ chemistry
Structure-Activity Relationship
HiBiT NRF2
Homology model
Nuclear factor erythroid 2-related factor 2
Target engagement
Ternary complex
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
15 Nov 2021
15 Nov 2021
Historique:
received:
16
04
2021
revised:
03
07
2021
accepted:
03
07
2021
pubmed:
25
7
2021
medline:
27
10
2021
entrez:
24
7
2021
Statut:
ppublish
Résumé
Pathway activating mutations of the transcription factor NRF2 and its negative regulator KEAP1 are strongly correlative with poor clinical outcome with pemetrexed/carbo(cis)platin/pembrolizumab (PCP) chemo-immunotherapy in lung cancer. Despite the strong genetic support and therapeutic potential for a NRF2 transcriptional inhibitor, currently there are no known direct inhibitors of the NRF2 protein or its complexes with MAF and/or DNA. Herein we describe the design of a novel and high-confidence homology model to guide a medicinal chemistry effort that resulted in the discovery of a series of peptides that demonstrate high affinity, selective binding to the Antioxidant Response Element (ARE) DNA and thereby displace NRF2-MAFG from its promoter, which is an inhibitory mechanism that to our knowledge has not been previously described. In addition to their activity in electrophoretic mobility shift (EMSA) and TR-FRET-based assays, we show significant dose-dependent ternary complex disruption of NRF2-MAFG binding to DNA by SPR, as well as cellular target engagement by thermal destabilization of HiBiT-tagged NRF2 in the NCI-H1944 NSCLC cell line upon digitonin permeabilization, and SAR studies leading to improved cellular stability. We report the characterization and unique profile of lead peptide 18, which we believe to be a useful in vitro tool to probe NRF2 biology in cancer cell lines and models, while also serving as an excellent starting point for additional in vivo optimization toward inhibition of NRF2-driven transcription to address a significant unmet medical need in non-small cell lung cancer (NSCLC).
Identifiants
pubmed: 34303079
pii: S0223-5234(21)00535-3
doi: 10.1016/j.ejmech.2021.113686
pii:
doi:
Substances chimiques
MafG Transcription Factor
0
NF-E2-Related Factor 2
0
Peptides
0
DNA
9007-49-2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
113686Informations de copyright
Copyright © 2021 Elsevier Masson SAS. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.