Thirty years of NRF2: advances and therapeutic challenges

Nature Reviews Drug Discovery, Год журнала: 2025, Номер unknown

Опубликована: Март 4, 2025

Язык: Английский

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Advances in developing noncovalent small molecules targeting Keap1

Drug Discovery Today, Год журнала: 2023, Номер 28(12), С. 103800 - 103800

Опубликована: Окт. 16, 2023

Kelch-like ECH-associated protein 1 (Keap1) is a drug target for diseases involving oxidative stress and inflammation. There are three covalent Keap1-binding drugs on the market, but noncovalent compounds that inhibit interaction between Keap1 nuclear factor erythroid 2-related 2 (Nrf2) represent an attractive alternative. Both compound types prevent degradation of Nrf2, leading to expression antioxidant antiinflammatory proteins. However, their off-target profiles differ as do exact pharmacodynamic effects. Here, we discuss opportunities challenges targeting with versus inhibitors. We then provide comprehensive overview current Keap1-Nrf2 inhibitors, focus pharmacological effects, examine therapeutic potential this class.

Язык: Английский

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Targeting kelch-like (KLHL) proteins: achievements, challenges and perspectives

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 269, С. 116270 - 116270

Опубликована: Фев. 29, 2024

Язык: Английский

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Targeted Protein Degradation (TPD) for Immunotherapy: Understanding Proteolysis Targeting Chimera-Driven Ubiquitin-Proteasome Interactions

Bioconjugate Chemistry, Год журнала: 2024, Номер 35(8), С. 1089 - 1115

Опубликована: Июль 11, 2024

Targeted protein degradation or TPD, is rapidly emerging as a treatment that utilizes small molecules to degrade proteins cause diseases. TPD allows for the selective removal of disease-causing proteins, including proteasome-mediated degradation, lysosome-mediated and autophagy-mediated degradation. This approach has shown great promise in preclinical studies now being translated treat numerous diseases, neurodegenerative infectious cancer. review discusses latest advances its potential new chemical modality immunotherapy, with special focus on innovative applications cutting-edge research PROTACs (Proteolysis TArgeting Chimeras) their efficient translation from scientific discovery technological achievements. Our also addresses significant obstacles prospects this domain, while offering insights into future immunotherapeutic applications.

Язык: Английский

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Deciphering Acetaminophen-Induced Hepatotoxicity: The Crucial Role of Transcription Factors like Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) as Genetic Determinants of Susceptibility to Drug-Induced Liver Injury

Drug Metabolism and Disposition, Год журнала: 2024, Номер 52(8), С. 740 - 753

Опубликована: Июнь 10, 2024

Acetaminophen (APAP) is the most commonly used over-the-counter medication throughout world. At therapeutic doses, APAP has potent analgesic and antipyretic effects. The efficacy safety of are influenced by multifactorial processes dependent upon dosing, namely frequency total dose. poisoning repeated ingestion supratherapeutic depletes glutathione stores in liver other organs capable metabolic bioactivation, leading to hepatocellular death due exhausted antioxidant defenses. Numerous genes, encompassing transcription factors signaling pathways, have been identified as playing pivotal roles toxicity, with being primary organ studied its central role metabolism injury. Nuclear factor erythroid 2-related 2 (NRF2) array downstream responsive genes crucial counteracting toxicity. NRF2, along negative regulator Kelch-like ECH-associated protein 1, plays a vital regulating intracellular redox homeostasis. This regulation significant modulating oxidative stress, inflammation, induced APAP. In this review, we provide an updated overview mechanisms through which NRF2 activation critically influence threshold for developing We also describe how genetically modified rodent models related underscoring significance response pathway. While focus, article comprehensively explores genetic involved phase I II APAP, pathways that contribute thereby providing holistic understanding landscape influencing susceptibility condition. SIGNIFICANCE STATEMENT: review summarizes elements underlying APAP-induced focusing on protective NRF2. delves into intricacies potential harm. It emphasizes need deeper insight molecular hepatotoxicity, especially interplay pathways.

Язык: Английский

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Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors

Journal of Medicinal Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Окт. 17, 2024

Inhibition of the protein-protein interaction between Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related 2 (Nrf2) has been recognized as an attractive approach for treating oxidative stress-related diseases. Here, we present a new series noncovalent Keap1-Nrf2 inhibitors developed by conformational restriction strategy our fluorenone-based compounds previously identified fragment-based drug discovery. The design was guided X-ray cocrystal structures, subsequent optimization process aimed at improving affinity, cellular activity, metabolic stability. From noncyclic compound

Язык: Английский

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CRBN‐PROTACs in Cancer Therapy: From Mechanistic Insights to Clinical Applications

Chemical Biology & Drug Design, Год журнала: 2024, Номер 104(5)

Опубликована: Ноя. 1, 2024

Cereblon (CRBN), a member of the E3 ubiquitin ligase complex, has gained significant attention as therapeutic target in cancer. CRBN regulates degradation various proteins cancer progression, including transcription factors and signaling molecules. PROTACs (proteolysis-targeting chimeras) are novel approach that uses cell's system to remove disease-causing selectively. CRBN-dependent work by tagging harmful for destruction through ubiquitin-proteasome system. This strategy offers several advantages over traditional protein inhibition methods, potential overcome drug resistance. Recent progress developing CRBN-based shown promising preclinical results both hematologic malignancies solid tumors. Additionally, have enhanced our understanding CRBN's role cancer, potentially serving biomarkers patient stratification predicting responses. In this review, we delineate mechanisms action (CRBN-PROTACs), summarize recent advances clinical applications, provide perspective on future development.

Язык: Английский

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Caffeic acid alleviates myocardial ischemia-reperfusion injury by directly targeting Keap1N532/M550 and promoting its degradation

Journal of Pharmaceutical Analysis, Год журнала: 2025, Номер unknown, С. 101219 - 101219

Опубликована: Янв. 1, 2025

Язык: Английский

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Patenting perspective on Keap1 inhibitors (2019-2024)

Expert Opinion on Therapeutic Patents, Год журнала: 2025, Номер unknown

Опубликована: Фев. 5, 2025

Introduction Kelch-like ECH-associated protein 1 (Keap1), an E3 ligase negatively regulating the nuclear factor erythroid 2-related 2 (Nrf2), has emerged as auspicious drug target for treating ailments associated with oxidative stress and inflammation. Discovery of Keap1 inhibitors have attracted significant interest.

Язык: Английский

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Compound K-Enriched Korean Red Ginseng Prevents Lung Cancer Progression by Targeting Cancer Cells and Fibroblasts

Journal of Ginseng Research, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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