Discovery of an allosteric 14-3-3 inhibitor for suppressing NRF2-driven cancer phenotypic screening and chemoproteomic-based target deconvolution.

The NRF2 transcription factor is constitutively active in various cancers, functioning as an oncogenic driver for tumor progression and chemo/radiotherapy resistance. Despite the well-documented role of NRF2 overactivation in cancer, no targeted therapy is currently available. In this study, using a combination of phenotypic screening, chemoproteomics, and biochemical and cellular assays, we identified WS3 as a potent allosteric inhibitor of 14-3-3 that selectively inhibits NRF2 activity in tumor cells.

Actinobacteria mediate anaerobic methane oxidation in iron-rich environment.

Recent research has identified the Actinobacterium Candidatus Mycobacterium methanotrophicum, which oxidizes methane aerobically in extremely acidic environments. In a previous study, we observed significant enrichment of Actinobacteria in an anaerobic iron-rich methane-oxidation reactor. Therefore, in this study, we assessed the anaerobic methane utilization potential of Actinobacteria using microcosm experiments, isotope labeling, and DNA stable isotope probing.

A High Dynamic Range and Fast Response Logarithmic Amplifier Employing Slope-Adjustment and Power-Down Mode.

Based on the GSMC 180 nm SiGe BiCMOS process, a parallel-summation logarithmic amplifier is presented in this paper. The logarithmic amplifier adopts a cascaded structure of nine-stage fully-differential limiting amplifiers (LA) to achieve high dynamic range. The ten-stage rectifier completes the conversion of amplified voltage to a logarithmic current signal.

Context-dependent anaerobic oxidation of methane: Insight for methane emission mitigation.

Anaerobic oxidation of methane (AOM) exhibits context-dependent metabolic versatility, governed by electron acceptor heterogeneity and anthropogenic perturbations. This study investigates the AOM potential by simulating three environments, high-dissolved organic carbon (DOC), high-nitrate with moderate sulfate, and sulfate-enhanced conditions, to investigate AOM potential under controlled perturbations. Substrate conversion dynamics were observed by monitoring the variation of methane, sulfate, nitrate, iron, etc.

Discovery of β-amino acid substituted naphthalene sulfonamide derivatives as potent Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) protein-protein interaction inhibitors for ulcerative colitis management.

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular defense system against oxidative insults. Directly inhibiting the Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 protein-protein interaction (PPI) has emerged as a promising approach to activate Nrf2 for the treatment of diseases associated with oxidative stress. Herein, we identified β-amino acids as privileged structural fragments for designing novel naphthalene sulfonamide-based Keap1-Nrf2 PPI inhibitors.

Patenting perspective on Keap1 inhibitors (2019-2024).

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

Areas Covered: This review covers patents on Keap1 inhibitors from 2019 to 2024, providing a comprehensive analysis of their structural characteristics, optimization strategies, pharmacological properties and clinical progress.

The accuracy of screening tools for sarcopenia in older Chinese adults: a systematic review and meta-analysis.

Objective: This review aimed to analyze and compare the accuracy of eight screening tools for sarcopenia in older Chinese adults according to different diagnostic criteria.

Methods: This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang databases were searched between the publication of the first expert consensus on sarcopenia in 2010 and April 2023 using relevant MeSH terms.

Bivalent inhibitors of the BTB E3 ligase KEAP1 enable instant NRF2 activation to suppress acute inflammatory response.

Most BTB-containing E3 ligases homodimerize to recognize a single substrate by engaging multiple degrons, represented by E3 ligase KEAP1 dimer and its substrate NRF2. Inactivating KEAP1 to hinder ubiquitination-dependent NRF2 degradation activates NRF2. While various KEAP1 inhibitors have been reported, all reported inhibitors bind to KEAP1 in a monovalent fashion and activate NRF2 in a lagging manner.

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

Nuclear factor erythroid 2-related factor 2 (NRF2) is a pleiotropic transcription factor which regulates the constitutive and inducible transcription of a wide array of genes and confers protection against a variety of pathologies. Directly disrupting Kelch-like ECH-associated protein 1 (KEAP1)-NRF2 protein-protein interaction (PPI) has been explored as a promising strategy to activate NRF2. We reported here the first identification of a series of 2-oxy-2-phenylacetic acid substituted naphthalene sulfonamide derivatives as potent KEAP1-NRF2 inhibitors.

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

Transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) and its negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (Keap1), control the redox and metabolic homeostasis and oxidative stress. Inhibitors of Keap1-Nrf2 interaction are promising in oxidative stress related inflammatory diseases but now hit hurdles. By utilizing thiazolidinone moiety to shield the key carboxyl pharmacophore in Keap1-Nrf2 inhibitor, a hydrogen peroxide (HO)-responsive prodrug pro2 was developed.

Azo-PROTAC: Novel Light-Controlled Small-Molecule Tool for Protein Knockdown.

Reversibly altering endogenous protein levels are persistent issues. Herein, we designed photoswitchable azobenzene-proteolysis targeting chimeras (Azo-PROTACs) by including azobenzene moieties between ligands for the E3 ligase and the protein of interest. Azo-PROTACs are light-controlled small-molecule tools for protein knockdown in cells.

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.

The transcription factor Nrf2 is a key regulator of cytoprotective system, and enhancing Nrf2 activity can protect cells from various insults and threats. Directly disrupting Keap1-Nrf2 protein-protein interactions has been regarded as a promising way to activate Nrf2. We reported here the first identification of amino acids as preferred substituents to design potent Keap1-Nrf2 inhibitors.

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

The Keap1-Nrf2-ARE pathway regulates the constitutive and inducible transcription of various genes that encode detoxification enzymes, antioxidant proteins and anti-inflammatory proteins and has pivotal roles in the defence against cellular oxidative stress. In this study, we investigated the therapeutic potential of CPUY192018, a potent small-molecule inhibitor of the Keap1-Nrf2 protein-protein interaction (PPI), in renal inflammation. In human proximal tubular epithelial HK-2 cells, CPUY192018 treatment significantly increased Nrf2 protein level and Nrf2 nuclear translocation, which enhanced Nrf2-ARE transcription capacity and the downstream protein content in a Nrf2 dependent manner.

Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Inhibition: An Emerging Strategy in Cancer Therapy.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pleiotropic transcription factor, especially for its complex and dual effects in cancer. With the continuous growing research, new regulatory modes and new functions of Nrf2 and tumor-promoting effects of Nrf2 in malignant transformed tumors have become increasingly clear. Accumulating evidence has established that Nrf2 contributes to the whole process of pathogenesis, progression, metastasis, and prognosis of cancer, and Nrf2 could be a promising target in cancer therapy.

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

Induced protein degradation by PROTACs has emerged as a promising strategy to target nonenzymatic proteins inside the cell. The aim of this study was to identify Keap1, a substrate adaptor protein for ubiquitin E3 ligase involved in oxidative stress regulation, as a novel candidate for PROTACs that can be applied in the degradation of the nonenzymatic protein Tau. A peptide PROTAC by recruiting Keap1-Cul3 ubiquitin E3 ligase was developed and applied in the degradation of intracellular Tau.

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

Directly disrupting Keap1-Nrf2 protein-protein interaction (PPI) has emerged as a novel way to activate Nrf2. Peptide Keap1-Nrf2 PPI inhibitors have been reported with high Keap1 binding affinity. However, these peptide inhibitors show weak activity in cells.

Discovery and Development of Kelch-like ECH-Associated Protein 1. Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction Inhibitors: Achievements, Challenges, and Future Directions.

The transcription factor Nrf2 is the primary regulator of the cellular defense system, and enhancing Nrf2 activity has potential usages in various diseases, especially chronic age-related and inflammatory diseases. Recently, directly targeting Keap1-Nrf2 protein-protein interaction (PPI) has been an emerging strategy to selectively and effectively activate Nrf2. This Perspective summarizes the progress in the discovery and development of Keap1-Nrf2 PPI inhibitors, including the Keap1-Nrf2 regulatory mechanisms, biochemical techniques for inhibitor identification, and approaches for identifying peptide and small-molecule inhibitors, as well as discusses privileged structures and future directions for further development of Keap1-Nrf2 PPI inhibitors.

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

Directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) has emerged as an attractive way to activate Nrf2, and Keap1-Nrf2 PPI inhibitors have been proposed as potential agents to relieve inflammatory and oxidative stress diseases. In this work, we investigated the diacetic moiety around the potent Keap1-Nrf2 PPI inhibitor DDO1018 (2), which was reported by our group previously. Exploration of bioisosteric replacements afforded the ditetrazole analog 7, which maintains the potent PPI inhibition activity (IC50 = 15.

Recent Advances in the Discovery of HIF-1α-p300/CBP Inhibitors as Anti-Cancer Agents.

Hypoxia-inducible factor-1 (HIF-1), a heterodimeric (containing α and β subunits) transcription factor, is involved in hypoxia response pathway that regulates the expression of many tumorrelated genes. The stabilized HIF-1 heterodimer couples to the general co-activators p300/CBP (CREB binding protein), forming an active transcription factor to initiate hypoxic responses. Inhibiting the transcription factor-coactivator HIF-1α-p300/CBP interaction represents an attractive approach for blocking hypoxia pathway in tumors.

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

Keap1 is a pluripotent protein which plays a predominant role in cellular homeostasis and stress responses. Given that the cellular environment is quite dynamic and versatile, further investigation of the function of Keap1 depends on tools for specific and real-time detection of Keap1. Herein, we report the development of functional affinity-based small-molecule probes which can overcome some shortcomings of current methods and be applied in further studying the function of Keap1.

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

Ulcerative colitis (UC) is a chronic relapsing-remitting form of inflammatory bowel disease (IBD) that increases the risk of colorectal cancer, the third most common malignancy in humans. Oxidative stress is a risk factor for the development of UC. The Keap1-Nrf2-ARE pathway is one of the most important defensive mechanisms against oxidative and/or electrophilic stresses.

The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update.

The Keap1-Nrf2-ARE ((Kelch-like ECH-Associating protein 1) nuclear factor erythroid 2 related factor 2-antioxidant response element) pathway is one of the most important defense mechanisms against oxidative and/or electrophilic stresses, and it is closely associated with inflammatory diseases, including cancer, neurodegenerative diseases, cardiovascular diseases, and aging. In recent years, progress has been made in strategies aimed at modulating the Keap1-Nrf2-ARE pathway. The Nrf2 activator DMF (Dimethylfumarates) has been approved by the FDA as a new first-line oral drug to treat patients with relapsing forms of multiple sclerosis, while a phase 3 study of another promising candidate, CDDO-Me, was terminated for safety reasons.

A systematic molecular dynamics approach to the study of peptide Keap1-Nrf2 protein-protein interaction inhibitors and its application to p62 peptides.

Protein-protein interactions (PPIs) as drug targets have been gaining growing interest, though developing drug-like small molecule PPI inhibitors remains challenging. Peptide PPI inhibitors, which can provide informative data on the PPI interface, are good starting points to develop small molecule modulators. Computational methods combining molecular dynamics simulations and binding energy calculations could give both the structural and the energetic perspective of peptide PPI inhibitors.

CPUY201112, a novel synthetic small-molecule compound and inhibitor of heat shock protein Hsp90, induces p53-mediated apoptosis in MCF-7 cells.

Heat-shock protein 90 (Hsp90) is highly expressed in many tumor cells and is associated with the maintenance of malignant phenotypes. Targeting Hsp90 has had therapeutic success in both solid and hematological malignancies, which has inspired more studies to identify new Hsp90 inhibitors with improved clinical efficacy. Using a fragment-based approach and subsequent structural optimization guided by medicinal chemistry principles, we identified the novel compound CPUY201112 as a potent Hsp90 inhibitor.

Escape, or Vanish: Control the Fate of p53 through MDM2-Mediated Ubiquitination.

p53 protein is a prominent tumor suppressor to induce cell cycle arrest, apoptosis and senescence, which attracts significant interest to cancer treatment. Therefore, it would be particularly important to restore the wild-type p53 that retains latent functions in the approximately 50% of tumors. MDM2 (murine double minute 2), the principal cellular antagonist of p53, has long been believed to suppress p53 activity through two main mechanisms: promoting degradation via its E3 ligase activity and masking p53 transcriptional activation by direct binding.