Design, synthesis, and evaluation of triazole derivatives that induce Nrf2 dependent gene products and inhibit the Keap1-Nrf2 protein-protein interaction

Hélène C. Bertrand; Marjolein Schaap; Liam Baird; Nikolaos D. Georgakopoulos; Adrian Fowkes; Clarisse Thiollier; Hiroko Kachi; Albena T. Dinkova-Kostova; Geoff Wells

doi:10.1021/acs.jmedchem.5b00602

Design, synthesis, and evaluation of triazole derivatives that induce Nrf2 dependent gene products and inhibit the Keap1-Nrf2 protein-protein interaction

Hélène C. Bertrand, Marjolein Schaap, Liam Baird, Nikolaos D. Georgakopoulos, Adrian Fowkes, Clarisse Thiollier, Hiroko Kachi, Albena T. Dinkova-Kostova, Geoff Wells (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

92 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	7186-7194
Number of pages	9
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	18
DOIs	https://doi.org/10.1021/acs.jmedchem.5b00602
Publication status	Published - 24 Sept 2015

Keywords

Cell Line, Tumor
Click chemistry
Computer simulation
Databases, Chemical
Dose-response relationship, Drug
Fluorescence polarization
HEK293 cells
Heme oxygenase-1
Humans
Intracellular signaling Peptides and Proteins
Isothiocyanates
Molecular docking simulation
NAD(P)H dehydrogenase (Quinone)
NF-E2-related factor 2
Protein binding
Structure-activity relationship
Triazoles

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery
Medicine(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.jmedchem.5b00602Licence: Other

Cite this

Bertrand, H. C., Schaap, M., Baird, L., Georgakopoulos, N. D., Fowkes, A., Thiollier, C., Kachi, H., Dinkova-Kostova, A. T., & Wells, G. (2015). Design, synthesis, and evaluation of triazole derivatives that induce Nrf2 dependent gene products and inhibit the Keap1-Nrf2 protein-protein interaction. Journal of Medicinal Chemistry, 58(18), 7186-7194. https://doi.org/10.1021/acs.jmedchem.5b00602

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abstract = "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.",

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Bertrand, HC, Schaap, M, Baird, L, Georgakopoulos, ND, Fowkes, A, Thiollier, C, Kachi, H, Dinkova-Kostova, AT & Wells, G 2015, 'Design, synthesis, and evaluation of triazole derivatives that induce Nrf2 dependent gene products and inhibit the Keap1-Nrf2 protein-protein interaction', Journal of Medicinal Chemistry, vol. 58, no. 18, pp. 7186-7194. https://doi.org/10.1021/acs.jmedchem.5b00602

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AU - Bertrand, Hélène C.

AU - Schaap, Marjolein

AU - Baird, Liam

AU - Georgakopoulos, Nikolaos D.

AU - Fowkes, Adrian

AU - Thiollier, Clarisse

AU - Kachi, Hiroko

AU - Dinkova-Kostova, Albena T.

AU - Wells, Geoff

PY - 2015/9/24

Y1 - 2015/9/24

N2 - 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.

AB - 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.

KW - Cell Line, Tumor

KW - Click chemistry

KW - Computer simulation

KW - Databases, Chemical

KW - Dose-response relationship, Drug

KW - Fluorescence polarization

KW - HEK293 cells

KW - Heme oxygenase-1

KW - Humans

KW - Intracellular signaling Peptides and Proteins

KW - Isothiocyanates

KW - Molecular docking simulation

KW - NAD(P)H dehydrogenase (Quinone)

KW - NF-E2-related factor 2

KW - Protein binding

KW - Structure-activity relationship

KW - Triazoles

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SN - 0022-2623

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SP - 7186

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JO - Journal of Medicinal Chemistry

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IS - 18

ER -

Design, synthesis, and evaluation of triazole derivatives that induce Nrf2 dependent gene products and inhibit the Keap1-Nrf2 protein-protein interaction

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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The Spatiotemporal Regulation of the Keap1/Nrf2 Pathway (Joint with University College London)

Cite this

Design, synthesis, and evaluation of triazole derivatives that induce Nrf2 dependent gene products and inhibit the Keap1-Nrf2 protein-protein interaction

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

The Spatiotemporal Regulation of the Keap1/Nrf2 Pathway (Joint with University College London)

Cite this