Advances in developing noncovalent small molecules targeting Keap1

Advances and challenges in therapeutic targeting of NRF2

(2023) Albena T. Dinkova-Kostova et al.   TRENDS IN PHARMACOLOGICAL SCIENCES

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

(2023) Dhulfiqar.Ali Abed et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Macrocycles in Drug Discovery─Learning from the Past for the Future

(2023) Diego Garcia Jimenez et al.   Journal of Medicinal Chemistry

Fragment-Based Discovery of Azocyclic Alkyl Naphthalenesulfonamides as Keap1-Nrf2 Inhibitors for Acute Lung Injury Treatment

(2023) Jianyu Yan et al.   Journal of Medicinal Chemistry

Omaveloxolone (SkyclarysTM) for patients with Friedreich’s ataxia

(2023) Sharadha Dayalan Naidu et al.   TRENDS IN PHARMACOLOGICAL SCIENCES

Methyl and Fluorine Effects in Novel Orally Bioavailable Keap1–Nrf2 PPI Inhibitor

(2023) Kazuki Otake et al.   ACS Medicinal Chemistry Letters

A potent phosphodiester Keap1-Nrf2 protein-protein interaction inhibitor as the efficient treatment of Alzheimer's disease

(2023) Yi Sun et al.   Redox Biology

Discovery of NAFLD-Improving Agents by Promoting the Degradation of Keap1

(2023) Mingming Qi et al.   JOURNAL OF MEDICINAL CHEMISTRY

Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Protein–Protein Interaction Inhibitors

(2023) Ziquan Zhao et al.   JOURNAL OF MEDICINAL CHEMISTRY

Minimizing the DILI potential of carboxylic acid-containing drugs: a perspective

(2023) Lars Weidolf et al.   MEDICINAL CHEMISTRY RESEARCH

Development of KEAP1-targeting PROTAC and its antioxidant properties: In vitro and in vivo

(2023) Se Yong Park et al.   Redox Biology

Importance of Binding Site Hydration and Flexibility Revealed When Optimizing a Macrocyclic Inhibitor of the Keap1–Nrf2 Protein–Protein Interaction

(2022) Fabio Begnini et al.   JOURNAL OF MEDICINAL CHEMISTRY

Phenyl Bis-Sulfonamide Keap1-Nrf2 Protein–Protein Interaction Inhibitors with an Alternative Binding Mode

(2022) Nikolaos Georgakopoulos et al.   JOURNAL OF MEDICINAL CHEMISTRY

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

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

(2022) Sumi Lee et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Crystallography-Guided Optimizations of the Keap1–Nrf2 Inhibitors on the Solvent Exposed Region: From Symmetric to Asymmetric Naphthalenesulfonamides

(2022) Guodong Liu et al.   JOURNAL OF MEDICINAL CHEMISTRY

The Role of KEAP1-NRF2 System in Atopic Dermatitis and Psoriasis

(2022) Tatsuya Ogawa et al.   Antioxidants

Design, synthesis and evaluation of novel small molecules acting as Keap1-Nrf2 protein-protein interaction inhibitors

(2022) Yunfeng Sun et al.   JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY

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

(2022) Enrique Crisman et al.   MEDICINAL RESEARCH REVIEWS

Development of Noncovalent Small-Molecule Keap1-Nrf2 Inhibitors by Fragment-Based Drug Discovery

(2022) Dilip Narayanan et al.   Journal of Medicinal Chemistry

Design and characterization of a heterobifunctional degrader of KEAP1

(2022) Hao Chen et al.   Redox Biology

Cell-Permeable PROTAC Degraders against KEAP1 Efficiently Suppress Hepatic Stellate Cell Activation through the Antioxidant and Anti-Inflammatory Pathway

(2022) Fengqin Wang et al.   ACS Pharmacology & Translational Science

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

Challenges and Limitations of Targeting the Keap1-Nrf2 Pathway for Neurotherapeutics: Bach1 De-Repression to the Rescue

(2021) Dmitry M. Hushpulian et al.   Frontiers in Aging Neuroscience

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

(2021) Yuta Horie et al.   Communications Biology

Optimization of 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acids as inhibitors of Keap1-Nrf2 protein-protein interaction to suppress neuroinflammation

(2021) Dhulfiqar Ali Abed et al.   BIOORGANIC & MEDICINAL CHEMISTRY

Recent Developments in PROTAC‐Mediated Protein Degradation: From Bench to Clinic

(2021) Zhenyi Hu et al.   CHEMBIOCHEM

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

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

Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation

(2021) Jieli Wei et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Targeting oxidative stress in disease: promise and limitations of antioxidant therapy

(2021) Henry Jay Forman et al.   NATURE REVIEWS DRUG DISCOVERY

Structure-based molecular hybridization design of Keap1-Nrf2 inhibitors as novel protective agents of acute lung injury

(2021) Le Zhang et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein−Protein Interaction

(2021) David Norton et al.   JOURNAL OF MEDICINAL CHEMISTRY

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

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

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

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

The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway

(2020) Liam Baird et al.   MOLECULAR AND CELLULAR BIOLOGY

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

Acyl glucuronide reactivity in perspective

(2020) Peter R. Bradshaw et al.   DRUG DISCOVERY TODAY

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

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

On the Clinical Pharmacology of Reactive Oxygen Species

(2020) Ana I. Casas et al.   PHARMACOLOGICAL REVIEWS

Bardoxolone conjugation enables targeted protein degradation of BRD4

(2020) Bingqi Tong et al.   Scientific Reports

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

Insight into the mechanism of action of dimethyl fumarate in multiple sclerosis

(2019) Sudhir Kumar Yadav et al.   JOURNAL OF MOLECULAR MEDICINE-JMM

Structure-Based Macrocycle Design in Small-Molecule Drug Discovery and Simple Metrics To Identify Opportunities for Macrocyclization of Small-Molecule Ligands

(2019) Maxwell D. Cummings et al.   JOURNAL OF MEDICINAL CHEMISTRY

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

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

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

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

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

Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway

(2018) Mengchen Lu et al.   EUROPEAN JOURNAL OF 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

Modulating NRF2 in Disease: Timing Is Everything

(2018) Matthew Dodson et al.   Annual Review of Pharmacology and Toxicology

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

Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming

(2018) David Olagnier et al.   Nature Communications

Identification of Novel Protein Targets of Dimethyl Fumarate Modification in Neurons and Astrocytes Reveals Actions Independent of Nrf2 Stabilization

(2018) Gerardo G. Piroli et al.   MOLECULAR & CELLULAR PROTEOMICS

Transcriptional Regulation by Nrf2

(2017) Claudia Tonelli et al.   ANTIOXIDANTS & REDOX SIGNALING

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

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

(2016) Ulf Schulze-Topphoff et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Chemical proteomic map of dimethyl fumarate–sensitive cysteines in primary human T cells

(2016) Megan M. Blewett et al.   Science Signaling

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

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

Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription

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

Chemical proteomic map of dimethyl fumarate–sensitive cysteines in primary human T cells

(2016) Megan M. Blewett et al.   Science Signaling

Dimethyl fumarate in the management of multiple sclerosis: appropriate patient selection and special considerations

(2016) Luca Prosperini et al.   Therapeutics and Clinical Risk Management

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

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

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

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

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

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

Mechanisms Contributing to Adverse Cardiovascular Events in Patients with Type 2 Diabetes Mellitus and Stage 4 Chronic Kidney Disease Treated with Bardoxolone Methyl

(2014) Melanie P. Chin et al.   AMERICAN JOURNAL OF NEPHROLOGY

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

(2014) Eric Jnoff et al.   ChemMedChem

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

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

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

Up-down Regulation of HO-1 and iNOS Gene Expressions by Ethyl Pyruvate via Recruiting p300 to Nrf2 and Depriving It from p65

(2013) Seung-Woo Kim et al.   FREE RADICAL BIOLOGY AND MEDICINE

Proteomic Analysis Shows Synthetic Oleanane Triterpenoid Binds to mTOR

(2011) Mark M. Yore et al.   PLoS One

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

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