ArticleSLAS discovery : advancing life sciences R & D2021
Development of a Homogeneous Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assay for the Inhibition of Keap1-Nrf2 Protein-Protein Interaction.
Article in SLAS discovery : advancing life sciences R & D, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 21 citations in OpenAlex.
- Design and optimisation of meta-substituted bis(arylsulfonamido)benzene inhibitors through a molecular hybridisation strategy targeting the Keap1-Nrf2 protein-protein interaction.Journal of enzyme inhibition and medicinal chemistry · 2026Article
- Biophysical and Biochemical Assays for Screening Small Molecule Inhibitors Targeting Toxin-Ribosome Interactions.Toxins · 2026Review
- Progress and Prospects in FRET for the Investigation of Protein-Protein Interactions.Biosensors · 2025Review
- Development of a high-throughput TR-FRET assay to identify inhibitors of the FAK-paxillin protein-protein interaction.SLAS discovery : advancing life sciences R & D · 2025Article
- Development of Biochemical and Cellular Probes to Study RIPK1 Target Engagement.ACS medicinal chemistry letters · 2024Article
- Structural modification of C2-substituents on 1,4-bis(arylsulfonamido)benzene or naphthalene-N,N'-diacetic acid derivatives as potent inhibitors of the Keap1-Nrf2 protein-protein interaction.European journal of medicinal chemistry · 2024Article
- New Insights into Antioxidant Peptides: An Overview of Efficient Screening, Evaluation Models, Molecular Mechanisms, and Applications.Antioxidants (Basel, Switzerland) · 2024Review
- Keap1-Nrf2 pathway: a key mechanism in the occurrence and development of cancer.Frontiers in oncology · 2024Review
- Optimization of the C2 substituents on the 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acid scaffold for better inhibition of Keap1-Nrf2 protein-protein interaction.European journal of medicinal chemistry · 2023Article
- Structure-activity relationships of 1,4-bis(arylsulfonamido)-benzene or naphthalene-N,N'-diacetic acids with varying C2-substituents as inhibitors of Keap1-Nrf2 protein-protein interaction.European journal of medicinal chemistry · 2022Article
- Bright and stable luminescent probes for target engagement profiling in live cells.Nature chemical biology · 2021Article
- Optimization of 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acids as inhibitors of Keap1-Nrf2 protein-protein interaction to suppress neuroinflammation.Bioorganic & medicinal chemistry · 2021Article
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4 authors at 3 institutions in 1 country.
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Abstract
The transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), plays a major role in regulating the antioxidant defense system through the Kelch-like ECH-associated protein 1-Nrf2-antioxidant response element (Keap1-Nrf2-ARE) pathway. Small-molecule inhibitors targeting Keap1-Nrf2 protein-protein interaction (PPI) decrease the rate of Nrf2 degradation by the 26S proteasome and thus increase the intracellular level of Nrf2, which translocates into the nucleus, leading to upregulated expression of cytoprotective and antioxidant enzymes. Such inhibitors can be developed into potential preventive and therapeutic agents of diseases caused by oxidative damage. To more effectively identify promising Nrf2 activators through the inhibition of Keap1-Nrf2 PPI, a homogeneous time-resolved fluorescence resonance energy transfer (TR-FRET) assay was developed in this work by indirectly labeling the Keap1 Kelch domain protein with Tb-anti-His antibody as the donor and using, as the acceptor, fluorescein isothiocyanate (FITC)-labeled 9mer Nrf2 peptide amide, the same fluorescent probe that was used in an earlier fluorescence polarization (FP) assay. Assay conditions, including concentrations of the various components, buffer type, and incubation time, were optimized in the TR-FRET competition assay with known small-molecule inhibitors of Keap1-Nrf2 PPI. Under the optimized conditions, the Keap1-Nrf2 TR-FRET assay exhibited great sensitivity with a high dynamic range and considerable stability for as long as 5 h. The Z' factor was determined to be 0.82, suggesting that the assay is suitable for high-throughput screening and lead optimization of inhibitors of Keap1-Nrf2 PPI. Furthermore, the TR-FRET assay is capable of differentiating potent inhibitors of Keap1-Nrf2 PPI down to the subnanomolar inhibition constant (
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