Design, Synthesis, and Evaluation of Triazole Derivatives That Induce Nrf2 Dependent Gene Products and Inhibit the Keap1-Nrf2 Protein-Protein Interaction.
The transcription factor Nrf2 regulates the expression of a large network of cytoprotective and metabolic enzymes and proteins. Compounds that directly and reversibly inhibit the interaction between Nrf2 and its main negative regulator Keap1 are potential pharmacological agents for a range of disease types including neurodegenerative conditions and cancer. We describe the development of a series of 1,4-diphenyl-1,2,3-triazole compounds that inhibit the Nrf2-Keap1 protein-protein interaction (PPI) in vitro and in live cells and up-regulate the expression of Nrf2-dependent gene products.
UCL School of Pharmacy, University College London , 29/39 Brunswick Square, London, WC1N 1AX, United Kingdom.
Hélène C
HC
Bertrand
UCL School of Pharmacy, University College London , 29/39 Brunswick Square, London, WC1N 1AX, United Kingdom.
Marjolein
M
Schaap
Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee , Dundee, DD1 9SY, Scotland, United Kingdom.
Liam
L
Baird
UCL School of Pharmacy, University College London , 29/39 Brunswick Square, London, WC1N 1AX, United Kingdom.
Nikolaos D
ND
Georgakopoulos
UCL School of Pharmacy, University College London , 29/39 Brunswick Square, London, WC1N 1AX, United Kingdom.
Adrian
A
Fowkes
UCL School of Pharmacy, University College London , 29/39 Brunswick Square, London, WC1N 1AX, United Kingdom.
Clarisse
C
Thiollier
UCL School of Pharmacy, University College London , 29/39 Brunswick Square, London, WC1N 1AX, United Kingdom.
Hiroko
H
Kachi
Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee , Dundee, DD1 9SY, Scotland, United Kingdom.|Departments of Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
Albena T
AT
Dinkova-Kostova
UCL School of Pharmacy, University College London , 29/39 Brunswick Square, London, WC1N 1AX, United Kingdom.
Geoff
G
Wells
D045744:Cell Line, Tumor; D057930:Click Chemistry; D003198:Computer Simulation; D062126:Databases, Chemical; D004305:Dose-Response Relationship, Drug; D005454:Fluorescence Polarization; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D017879:Isothiocyanates / Q000737:chemistry / Q000494:pharmacology; D000072019:Kelch-Like ECH-Associated Protein 1; D062105:Molecular Docking Simulation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis* / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013454:Sulfoxides; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D047908:Intracellular Signaling Peptides and Proteins; D017879:Isothiocyanates; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D013454:Sulfoxides; D014230:Triazoles; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C016766:sulforaphane