Track topics on Twitter Track topics that are important to you
Inhibiting the protein-protein interaction (PPI) between the transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including CNS disorders. Numerous non-covalent small-molecule Keap1-Nrf2 PPI inhibitors have been reported to date, but many feature suboptimal physicochemical properties for permeating the blood-brain barrier, while others contain problematic structural moieties. Here, we present the first side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence polarization (FP), thermal shift assay (TSA), and surface plasmon resonance (SPR)-and further evaluate the compounds in an NQO1 induction cell assay and in counter tests for non-specific activities. Surprisingly, half of the compounds were inactive or deviated substantially from reported activities, while we confirm the cross-assay activities for others. Through this study, we have identified the most promising Keap1-Nrf2 inhibitors that can serve as pharmacological probes or starting points for developing CNS active Keap1 inhibitors.
This article was published in the following journal.
Name: Journal of medicinal chemistry
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 pivot...
Various phytochemicals have been reported to protect against oxidative stress. However, the mechanism underlying has not been systematically evaluated, which limited their application in disease treat...
Kelch-like ECH-associated protein 1 (KEAP1), as a negative regulator of nuclear factor erythroid 2 like 2 ( NRF2), plays a pivotal role in NRF2 signaling pathway and involves in tumorigenesis. Polymor...
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.
The KEAP1/NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signalling during chronic oxidative stress may be associated with the pathophysiology of se...
Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) proteins work in concert to regulate the levels of reactive oxygen species (ROS). The Keap1-Nrf2 anti...
This phase II trial studies how well glutaminase inhibitor CB-839 hydrochloride (CB-839 HCl) works in treating patients with specific genetic mutations and solid tumors or malignant periph...
Oxidative stress and inflammation are cardiovascular risk factors in patients with chronic kidney disease (CKD) undergoing hemodialysis (HD). Nuclear transcription factors play roles in th...
The objective of this study is to evaluate the safety and preliminary efficacy of three doses of Cand5. Cand5, a small interfering RNA molecule that selectively silences the mRNA encoding...
A pilot study has been designed to determine (primary objective) if three brief interventions with three oral BSE regimens will alter mRNA biomarkers of Nrf2 pathway signaling, including N...
The purpose of this study is to evaluate the pharmacokinetics, safety and preliminary efficacy of 3 doses of Cand5. Cand5 is a small interfering RNA molecule that selectively silences the...
Part of a MESSENGER RNA molecule that undergoes a conformation change upon binding a specific metabolite or other small molecule thereby regulating the messenger RNA's transcription, post-transcriptional processing, transport, translation, or stability in response to varying levels of the metabolite or other small molecule.
The study of the similarities and differences in the structures of homologous tissues across various species.
Comparison of outcomes, results, responses, etc for different techniques, therapeutic approaches or other inputs.
The comparative study of animal structure with regard to homologous organs or parts. (Stedman, 25th ed)
A small maf protein that forms dimers with NRF1 protein; NRF2 PROTEIN; and P45 NF-E2 PROTEIN. MafF complexes bind Maf recognition elements to regulate tissue-specific GENETIC TRANSCRIPTION.
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...