KEAP1‐NRF2 protein–protein interaction inhibitors: Design, pharmacological properties and therapeutic potential

The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity

(2022) Laura Casares et al.   Redox Biology

Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds

(2021) Jakob S. Pallesen et al.   JOURNAL OF MEDICINAL CHEMISTRY

Identification of novel inhibitors of Keap1/Nrf2 by a promising method combining protein–protein interaction-oriented library and machine learning

(2021) Yugo Shimizu et al.   Scientific Reports

Molecular basis for the disruption of Keap1–Nrf2 interaction via Hinge & Latch mechanism

(2021) Yuta Horie et al.   Communications Biology

Developing a novel strategy for COPD therapy by targeting Nrf2 and metabolism reprogramming simultaneously

(2021) Li Wang et al.   FREE RADICAL BIOLOGY AND MEDICINE

A bioactive ligand-conjugated iridium(III) metal-based complex as a Keap1–Nrf2 protein-protein interaction inhibitor against acetaminophen-induced acute liver injury

(2021) Guodong Li et al.   Redox Biology

Discovery of disubstituted xylylene derivatives as small molecule direct inhibitors of Keap1-Nrf2 protein-protein interaction

(2020) Dhulfiqar Ali Abed et al.   BIOORGANIC & MEDICINAL CHEMISTRY

Inhibitors of the protein–protein interaction between phosphorylated p62 and Keap1 attenuate chemoresistance in a human hepatocellular carcinoma cell line

(2020) Daisuke Yasuda et al.   FREE RADICAL RESEARCH

Synthesis and Evaluation of Noncovalent Naphthalene-Based KEAP1-NRF2 Inhibitors

(2020) Phillip R. Lazzara et al.   ACS Medicinal Chemistry Letters

MOrPH-PhD: An Integrated Phage Display Platform for the Discovery of Functional Genetically Encoded Peptide Macrocycles

(2020) Andrew E. Owens et al.   ACS Central Science

Beyond repression of Nrf2: An update on Keap1

(2020) Aleksandra Kopacz et al.   FREE RADICAL BIOLOGY AND MEDICINE

Emerging Substrate Proteins of Kelch-like ECH Associated Protein 1 (Keap1) and Potential Challenges for the Development of Small-Molecule Inhibitors of the Keap1-Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Protein–Protein Interaction

(2020) Yong Zhang et al.   JOURNAL OF MEDICINAL CHEMISTRY

Nrf2 activation through the inhibition of Keap1–Nrf2 protein–protein interaction

(2020) Sumi Lee et al.   MEDICINAL CHEMISTRY RESEARCH

An open-source drug discovery platform enables ultra-large virtual screens

(2020) Christoph Gorgulla et al.   NATURE

Nrf2 activator via interference of Nrf2-Keap1 interaction has antioxidant and anti-inflammatory properties in Parkinson's disease animal model

(2020) Siwon Kim et al.   NEUROPHARMACOLOGY

Combined Peptide and Small-Molecule Approach toward Nonacidic THIQ Inhibitors of the KEAP1/NRF2 Interaction

(2020) Jesus M. Ontoria et al.   ACS Medicinal Chemistry Letters

A hydrogen peroxide responsive prodrug of Keap1-Nrf2 inhibitor for improving oral absorption and selective activation in inflammatory conditions

(2020) Mengchen Lu et al.   Redox Biology

Direct inhibition of Keap1-Nrf2 Protein-Protein interaction as a potential therapeutic strategy for Alzheimer's disease

(2020) Yi Sun et al.   BIOORGANIC CHEMISTRY

Recent progress in Keap1-Nrf2 protein-protein interaction inhibitors

(2020) Yi Mou et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Design, Synthesis, and Structure–Activity Relationships of Indoline-Based Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-Like 2 (Keap1-Nrf2) Protein–Protein Interaction Inhibitors

(2020) Hai-Shan Zhou et al.   JOURNAL OF MEDICINAL CHEMISTRY

Discovery of 2-oxy-2-phenylacetic acid substituted naphthalene sulfonamide derivatives as potent KEAP1-NRF2 protein-protein interaction inhibitors for inflammatory conditions

(2020) Meng-Chen Lu et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Mining Natural Products for Macrocycles to Drug Difficult Targets

(2020) Fabio Begnini et al.   JOURNAL OF MEDICINAL CHEMISTRY

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

(2019) Antonio Cuadrado et al.   NATURE REVIEWS DRUG DISCOVERY

Structure–Activity and Structure–Conformation Relationships of Aryl Propionic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1/Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1/NRF2) Protein–Protein Interaction

(2019) Tom D. Heightman et al.   JOURNAL OF MEDICINAL CHEMISTRY

Discovery of a Potent Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Protein–Protein Interaction Inhibitor with Natural Proline Structure as a Cytoprotective Agent against Acetaminophen-Induced Hepatotoxicity

(2019) Meng-Chen Lu et al.   JOURNAL OF MEDICINAL CHEMISTRY

Emerging Screening Approaches in the Development of Nrf2–Keap1 Protein–Protein Interaction Inhibitors

(2019) Chung-Hang Leung et al.   INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity

(2019) Kim T. Tran et al.   JOURNAL OF MEDICINAL CHEMISTRY

CPUY192018, a potent inhibitor of the Keap1-Nrf2 protein-protein interaction, alleviates renal inflammation in mice by restricting oxidative stress and NF-κB activation

(2019) Meng-Chen Lu et al.   Redox Biology

Inhibition of the Keap1-Nrf2 protein-protein interaction protects retinal cells and ameliorates retinal ischemia-reperfusion injury

(2019) Qiaoyan Hui et al.   FREE RADICAL BIOLOGY AND MEDICINE

Isoquinoline Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-like 2 (KEAP1-NRF2) Inhibitors with High Metabolic Stability

(2019) Phillip R. Lazzara et al.   JOURNAL OF MEDICINAL CHEMISTRY

Development of a Cell-Permeable Cyclic Peptidyl Inhibitor against the Keap1–Nrf2 Interaction

(2019) Heba Salim et al.   JOURNAL OF ORGANIC CHEMISTRY

Design, synthesis and identification of novel, orally bioavailable non-covalent Nrf2 activators

(2019) Bin Ma et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Rutaecarpine inhibits KEAP1-NRF2 interaction to activate NRF2 and ameliorate dextran sulfate sodium-induced colitis

(2019) Youbo Zhang et al.   FREE RADICAL BIOLOGY AND MEDICINE

Opsonic Phagocytosis in Chronic Obstructive Pulmonary Disease is Enhanced by Nrf2 Agonists.

(2018) Martin A Bewley et al.   AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A

(2018) Marta Pajares et al.   Autophagy

Perfluoroarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction

(2018) Richard J. Steel et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

NRF2 and the Hallmarks of Cancer

(2018) Montserrat Rojo de la Vega et al.   CANCER CELL

Modified Peptide Inhibitors of the Keap1-Nrf2 Protein-Protein Interaction Incorporating Unnatural Amino Acids

(2018) Nikolaos D. Georgakopoulos et al.   CHEMBIOCHEM

Discovery of a head-to-tail cyclic peptide as the Keap1-Nrf2 protein-protein interaction inhibitor with high cell potency

(2018) Meng-Chen Lu et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Fragment-growing guided design of Keap1-Nrf2 protein-protein interaction inhibitors for targeting myocarditis

(2018) Ning Meng et al.   FREE RADICAL BIOLOGY AND MEDICINE

Hyperactivation of Nrf2 leads to hypoplasia of bone in vivo

(2018) Eiki Yoshida et al.   GENES TO CELLS

Identification of a novel small-molecule Keap1–Nrf2 PPI inhibitor with cytoprotective effects on LPS-induced cardiomyopathy

(2018) Cheng-Shi Jiang et al.   JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY

Non-covalent Small-Molecule Kelch-like ECH-Associated Protein 1–Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Inhibitors and Their Potential for Targeting Central Nervous System Diseases

(2018) Jakob S. Pallesen et al.   JOURNAL OF MEDICINAL CHEMISTRY

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

(2018) Antonio Cuadrado et al.   PHARMACOLOGICAL REVIEWS

The mycosporine-like amino acids porphyra-334 and shinorine are antioxidants and direct antagonists of Keap1-Nrf2 binding

(2018) Ranko Gacesa et al.   BIOCHIMIE

Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors

(2018) Benjamin G. Richardson et al.   JOURNAL OF MEDICINAL CHEMISTRY

Selective autophagy as a potential therapeutic target for neurodegenerative disorders

(2018) Aurora Scrivo et al.   LANCET NEUROLOGY

Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation

(2018) Eleni N. Tsakiri et al.   AGING CELL

Rational cyclization-based minimization of entropy penalty upon the binding of Nrf2-derived linear peptides to Keap1: A new strategy to improve therapeutic peptide activity against sepsis

(2018) Ke Chen et al.   BIOPHYSICAL CHEMISTRY

Direct inhibition of Keap1–Nrf2 interaction by egg-derived peptides DKK and DDW revealed by molecular docking and fluorescence polarization

(2017) Liangyu Li et al.   RSC Advances

Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy

(2017) Nikolaos D. Georgakopoulos et al.   Scientific Reports

Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer’s disease

(2017) Fiona Kerr et al.   PLoS Genetics

Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors

(2016) Anju Singh et al.   ACS Chemical Biology

Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes

(2016) Marta Pajares et al.   Autophagy

Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity

(2016) Daisuke Yasuda et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Design, Synthesis, and Initial Evaluation of Affinity-Based Small-Molecule Probes for Fluorescent Visualization and Specific Detection of Keap1

(2016) Mengchen Lu et al.   JOURNAL OF MEDICINAL CHEMISTRY

Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein–Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery

(2016) Thomas G. Davies et al.   JOURNAL OF MEDICINAL CHEMISTRY

The status of Nrf2-based therapeutics: current perspectives and future prospects

(2016) IrinaG Gazaryan et al.   Neural Regeneration Research

Nrf2–ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases

(2016) Izaskun Buendia et al.   PHARMACOLOGY & THERAPEUTICS

Kidney epithelium specific deletion of kelch-like ECH-associated protein 1 (Keap1) causes hydronephrosis in mice

(2016) Sanjeev Noel et al.   BMC Nephrology

Polar Recognition Group Study of Keap1-Nrf2 Protein–Protein Interaction Inhibitors

(2016) Meng-Chen Lu et al.   ACS Medicinal Chemistry Letters

p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming

(2016) Tetsuya Saito et al.   Nature Communications

Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription

(2016) Eri H. Kobayashi et al.   Nature Communications

An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis

(2016) Meng-Chen Lu et al.   Scientific Reports

Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways

(2015) Joanna D. Wardyn et al.   BIOCHEMICAL SOCIETY TRANSACTIONS

Modulating protein–protein interactions: the potential of peptides

(2015) Laura Nevola et al.   CHEMICAL COMMUNICATIONS

Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators

(2015) Atul D. Jain et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Structural basis of Keap1 interactions with Nrf2

(2015) Peter Canning et al.   FREE RADICAL BIOLOGY AND MEDICINE

Activation of NRF2 Signaling in HEK293 Cells by a First-in-Class Direct KEAP1-NRF2 Inhibitor

(2015) Xia Wen et al.   JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY

Characterization of RA839, a Noncovalent Small Molecule Binder to Keap1 and Selective Activator of Nrf2 Signaling

(2015) Angelika F. Winkel et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

ZINC 15 – Ligand Discovery for Everyone

(2015) Teague Sterling et al.   Journal of Chemical Information and Modeling

Structure–Activity and Structure–Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1–Nrf2 Protein–Protein Interaction Inhibitor

(2015) Zheng-Yu Jiang et al.   JOURNAL OF MEDICINAL CHEMISTRY

Design, Synthesis, and Evaluation of Triazole Derivatives That Induce Nrf2 Dependent Gene Products and Inhibit the Keap1–Nrf2 Protein–Protein Interaction

(2015) Hélène C. Bertrand et al.   JOURNAL OF MEDICINAL CHEMISTRY

DMF, but not other fumarates, inhibits NF-κB activity in vitro in an Nrf2-independent manner

(2015) Geoffrey O. Gillard et al.   JOURNAL OF NEUROIMMUNOLOGY

Cell-Permeable Peptide Targeting the Nrf2-Keap1 Interaction: A Potential Novel Therapy for Global Cerebral Ischemia

(2015) J. Tu et al.   JOURNAL OF NEUROSCIENCE

Multiple binding modes of a small molecule to human Keap1 revealed by X-ray crystallography and molecular dynamics simulation

(2015) Mikiya Satoh et al.   FEBS Open Bio

Dimethyl Fumarate and Monoethyl Fumarate Exhibit Differential Effects on KEAP1, NRF2 Activation, and Glutathione Depletion In Vitro

(2015) Melanie S. Brennan et al.   PLoS One

The PTEN/NRF2 Axis Promotes Human Carcinogenesis

(2014) Ana I. Rojo et al.   ANTIOXIDANTS & REDOX SIGNALING

Monitoring Keap1–Nrf2 interactions in single live cells

(2014) Liam Baird et al.   BIOTECHNOLOGY ADVANCES

PMI: A ΔΨm Independent Pharmacological Regulator of Mitophagy

(2014) Daniel A. East et al.   CHEMISTRY & BIOLOGY

Binding Mode and Structure-Activity Relationships around Direct Inhibitors of the Nrf2-Keap1 Complex

(2014) Eric Jnoff et al.   ChemMedChem

Rapid Identification of Keap1–Nrf2 Small-Molecule Inhibitors through Structure-Based Virtual Screening and Hit-Based Substructure Search

(2014) Chunlin Zhuang et al.   JOURNAL OF MEDICINAL CHEMISTRY

Discovery of Potent Keap1–Nrf2 Protein–Protein Interaction Inhibitor Based on Molecular Binding Determinants Analysis

(2014) Zheng-Yu Jiang et al.   JOURNAL OF MEDICINAL CHEMISTRY

Structure of the BTB Domain of Keap1 and Its Interaction with the Triterpenoid Antagonist CDDO

(2014) Anne Cleasby et al.   PLoS One

Induction of Heme Oxygenase I (HMOX1) by HPP-4382: A Novel Modulator of Bach1 Activity

(2014) Otis C. Attucks et al.   PLoS One

The Nrf2 regulatory network provides an interface between redox and intermediary metabolism

(2014) John D. Hayes et al.   TRENDS IN BIOCHEMICAL SCIENCES

Role of Nrf2 in Oxidative Stress and Toxicity

(2013) Qiang Ma   Annual Review of Pharmacology and Toxicology

Reactive Oxygen Species in Inflammation and Tissue Injury

(2013) Manish Mittal et al.   ANTIOXIDANTS & REDOX SIGNALING

Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism

(2013) Douglas Marcotte et al.   BIOORGANIC & MEDICINAL CHEMISTRY

Discovery of a small-molecule inhibitor and cellular probe of Keap1–Nrf2 protein–protein interaction

(2013) Longqin Hu et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Structural Basis for Cul3 Protein Assembly with the BTB-Kelch Family of E3 Ubiquitin Ligases

(2013) Peter Canning et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Kinetic, Thermodynamic, and Structural Characterizations of the Association between Nrf2-DLGex Degron and Keap1

(2013) Toshiaki Fukutomi et al.   MOLECULAR AND CELLULAR BIOLOGY

CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation

(2013) Frederick J Sheedy et al.   NATURE IMMUNOLOGY

Peptide inhibitors of the Keap1–Nrf2 protein–protein interaction with improved binding and cellular activity

(2013) Rowena Hancock et al.   ORGANIC & BIOMOLECULAR CHEMISTRY

Novel protein–protein interaction inhibitor of Nrf2–Keap1 discovered by structure-based virtual screening

(2013) Hao-Peng Sun et al.   MedChemComm

Targeting Nrf2-Mediated Gene Transcription by Extremely Potent Synthetic Triterpenoids Attenuate Dopaminergic Neurotoxicity in the MPTP Mouse Model of Parkinson's Disease

(2012) Navneet Ammal Kaidery et al.   ANTIOXIDANTS & REDOX SIGNALING

Features of protein–protein interactions that translate into potent inhibitors: topology, surface area and affinity

(2012) Matthew C. Smith et al.   EXPERT REVIEWS IN MOLECULAR MEDICINE

Synthesis, Chemical Reactivity as Michael Acceptors, and Biological Potency of Monocyclic Cyanoenones, Novel and Highly Potent Anti-inflammatory and Cytoprotective Agents

(2012) Suqing Zheng et al.   JOURNAL OF MEDICINAL CHEMISTRY

Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity

(2012) S Chowdhry et al.   ONCOGENE

Anti-inflammatory Effect of a Cell-Penetrating Peptide Targeting the Nrf2/Keap1 Interaction

(2012) Richard Steel et al.   ACS Medicinal Chemistry Letters

A novel strategy to activate cytoprotective genes in the injured brain

(2011) Jing Zhao et al.   BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway

(2011) Ralf A. Linker et al.   BRAIN

Kinetic Analyses of Keap1-Nrf2 Interaction and Determination of the Minimal Nrf2 Peptide Sequence Required for Keap1 Binding Using Surface Plasmon Resonance

(2011) Yu Chen et al.   Chemical Biology & Drug Design

Peptide inhibitors of the Keap1–Nrf2 protein–protein interaction

(2011) Rowena Hancock et al.   FREE RADICAL BIOLOGY AND MEDICINE

Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis

(2011) Gina M. DeNicola et al.   NATURE

Suppression of NF-κB signaling by KEAP1 regulation of IKKβ activity through autophagic degradation and inhibition of phosphorylation

(2010) Jeong-Eun Kim et al.   CELLULAR SIGNALLING

Nrf2 Expression Is Regulated by Epigenetic Mechanisms in Prostate Cancer of TRAMP Mice

(2010) Siwang Yu et al.   PLoS One

Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1

(2009) Aimee L. Eggler et al.   BIOCHEMICAL JOURNAL

Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1–NRF2 pathway, and not the BACH1–NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds

(2009) A.Kenneth MacLeod et al.   CARCINOGENESIS

Acetylation of Nrf2 by p300/CBP Augments Promoter-Specific DNA Binding of Nrf2 during the Antioxidant Response

(2009) Z. Sun et al.   MOLECULAR AND CELLULAR BIOLOGY

NF-κB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK

(2008) Guang-Hui Liu et al.   BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH

Covalent Modification at Cys151 Dissociates the Electrophile Sensor Keap1 from the Ubiquitin Ligase CUL3

(2008) Girish Rachakonda et al.   CHEMICAL RESEARCH IN TOXICOLOGY