ArticleBioorganic & medicinal chemistry letters2013
Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction.
Article in Bioorganic & medicinal chemistry letters, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
What it found
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The trial behind it
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Who cites it
89 citing papers in PubMed.
- 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
- Arctigenin discovered by high-throughput screening ameliorates doxorubicin-induced cardiotoxicity as a novel natural KEAP1-NRF2 inhibitor.Journal of pharmaceutical analysis · 2026Article
- Perm1 enhances Nrf2-driven antioxidant defense through Keap1 oxidation during myocardial ischemia/reperfusion injury.JCI insight · 2026Article
- Isolation of Secondary Metabolites fromPlants (Basel, Switzerland) · 2026Article
- Beyond KEAP1: The Context-Specific NRF2 Partner Code in Disease and Therapy.Antioxidants (Basel, Switzerland) · 2026Review
- Article
- Dose-Related Structural and Functional Modifications of Mitochondria Are Induced In Vitro by Low Ozone Concentrations.International journal of molecular sciences · 2026Article
- Discovery of a novel Keap1 inhibitor for neurodegeneration through virtual screening and molecular dynamics simulations.PloS one · 2026Article
- Article
- CB5712809, a novel Keap1 inhibitor upregulates SQSTM1/p62 mediated Nrf2 activation to induce cell death in colon cancer cells.Discover oncology · 2025Article
- Health position paper and redox perspectives - Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases.Redox biology · 2025Review
- PPIA dictates NRF2 stability to promote lung cancer progression.Nature communications · 2024Article
- Strategies for converting turn-motif and cyclic peptides to small molecules for targeting protein-protein interactions.RSC chemical biology · 2024Review
- 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
- Emerging small molecule inhibitors of Bach1 as therapeutic agents: Rationale, recent advances, and future perspectives.BioEssays : news and reviews in molecular, cellular and developmental biology · 2024Article
- Andrographolide attenuated MCT-induced HSOS via regulating NRF2-initiated mitochondrial biogenesis and antioxidant response.Cell biology and toxicology · 2023Article
- Function, mechanism and drug discovery of ubiquitin and ubiquitin-like modification with multiomics profiling for cancer therapy.Acta pharmaceutica Sinica. B · 2023Review
- Mitochondrial Features of Mouse Myoblasts Are Finely Tuned by Low Doses of Ozone: The Evidence In Vitro.International journal of molecular sciences · 2023Article
- Methyl and Fluorine Effects in Novel Orally Bioavailable Keap1-Nrf2 PPI Inhibitor.ACS medicinal chemistry letters · 2023Article
- Targeting Protein-Protein Interfaces with Peptides: The Contribution of Chemical Combinatorial Peptide Library Approaches.International journal of molecular sciences · 2023Review
29 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors.
Funding
Abstract
A high-throughput screen (HTS) of the MLPCN library using a homogenous fluorescence polarization assay identified a small molecule as a first-in-class direct inhibitor of Keap1-Nrf2 protein-protein interaction. The HTS hit has three chiral centers; a combination of flash and chiral chromatographic separation demonstrated that Keap1-binding activity resides predominantly in one stereoisomer (SRS)-5 designated as ML334 (LH601A), which is at least 100× more potent than the other stereoisomers. The stereochemistry of the four cis isomers was assigned using X-ray crystallography and confirmed using stereospecific synthesis. (SRS)-5 is functionally active in both an ARE gene reporter assay and an Nrf2 nuclear translocation assay. The stereospecific nature of binding between (SRS)-5 and Keap1 as well as the preliminary but tractable structure-activity relationships support its use as a lead for our ongoing optimization.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.