Dataset Information

Identification of novel indole derivatives acting as inhibitors of the Keap1-Nrf2 interaction.

ABSTRACT: Nine indole derivatives (9a-i) were tested as potential inhibitors of the Keap1-Nrf2 interaction. This class of compounds increases the intracellular levels of the transcription factor Nrf2 and the consequent expression of enzymes encoded by genes containing the antioxidant response element (ARE). In the ARE-luciferase reporter assay only 9e-g revealed to be remarkably more active than t-butylhydroxyquinone (t-BHQ), with 9g standing out as the best performing compound. While 9e and 9f are weak acids, 9g is an ampholyte prevailing as a zwitterion in neutral aqueous solutions. The ability of 9e-g to significantly increase levels of Nrf2, NADPH:quinone oxidoreductase 1, and transketolase (TKT) gave further support to the hypothesis that these compounds act as inhibitors of the Keap1-Nrf2 interaction. Docking simulations allowed us to elucidate the nature of the putative interactions between 9g and Keap1.

SUBMITTER: Cosimelli B

PROVIDER: S-EPMC6567006 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of novel indole derivatives acting as inhibitors of the Keap1-Nrf2 interaction.

Cosimelli Barbara B Greco Giovanni G Laneri Sonia S Novellino Ettore E Sacchi Antonia A Amendola Giorgio G Cosconati Sandro S Bortolozzi Roberta R Viola Giampietro G

Journal of enzyme inhibition and medicinal chemistry 20191201 1

Nine indole derivatives (9a-i) were tested as potential inhibitors of the Keap1-Nrf2 interaction. This class of compounds increases the intracellular levels of the transcription factor Nrf2 and the consequent expression of enzymes encoded by genes containing the antioxidant response element (ARE). In the ARE-luciferase reporter assay only 9e-g revealed to be remarkably more active than t-butylhydroxyquinone (t-BHQ), with 9g standing out as the best perfo ...[more]

PMID: 31179771

Similar Datasets

Project description:BackgroundNuclear factor erythroid-2 related factor 2 (NRF2) is a redox-sensitive transcription factor that positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation. Increased expression of cellular antioxidants and xenobiotic detoxification enzymes has been implicated in resistance of tumor cells against chemotherapeutic drugs.Methods and findingsHere we report a systematic analysis of the KEAP1 genomic locus in lung cancer patients and cell lines that revealed deletion, insertion, and missense mutations in functionally important domains of KEAP1 and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event. Sequencing of KEAP1 in 12 cell lines and 54 non-small-cell lung cancer (NSCLC) samples revealed somatic mutations in KEAP1 in a total of six cell lines and ten tumors at a frequency of 50% and 19%, respectively. All the mutations were within highly conserved amino acid residues located in the Kelch or intervening region domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity. Evaluation of loss of heterozygosity at 19p13.2 revealed allelic losses in 61% of the NSCLC cell lines and 41% of the tumor samples. Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps.ConclusionsThis is the first study to our knowledge to demonstrate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC. Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer suggests that tumor cells manipulate the NRF2 pathway for their survival against chemotherapeutic agents.

Dataset Information

Identification of novel indole derivatives acting as inhibitors of the Keap1-Nrf2 interaction.

Publications

Identification of novel indole derivatives acting as inhibitors of the Keap1-Nrf2 interaction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets