A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity

Research output: Contribution to journal › Journal article › Research › peer-review

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A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors : Chemical Synthesis, Binding Properties, and Cellular Activity. / Tran, Kim Tai; Pallesen, Jakob S; Solbak, Sara Marie Øie; Narayanan, Dilip; Baig, Amina; Zang, Jie; Aguayo-Orozco, Alejandro; Carmona, Rosa; Garcia, Anthony; Bach, Anders.

In: Journal of Medicinal Chemistry, Vol. 62, No. 17, 2019, p. 8028-8052.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Tran, KT, Pallesen, JS, Solbak, SMØ, Narayanan, D, Baig, A, Zang, J, Aguayo-Orozco, A, Carmona, R, Garcia, A & Bach, A 2019, 'A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity', Journal of Medicinal Chemistry, vol. 62, no. 17, pp. 8028-8052. https://doi.org/10.1021/acs.jmedchem.9b00723

APA

Tran, K. T., Pallesen, J. S., Solbak, S. M. Ø., Narayanan, D., Baig, A., Zang, J., Aguayo-Orozco, A., Carmona, R., Garcia, A., & Bach, A. (2019). A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity. Journal of Medicinal Chemistry, 62(17), 8028-8052. https://doi.org/10.1021/acs.jmedchem.9b00723

Vancouver

Tran KT, Pallesen JS, Solbak SMØ, Narayanan D, Baig A, Zang J et al. A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity. Journal of Medicinal Chemistry. 2019;62(17):8028-8052. https://doi.org/10.1021/acs.jmedchem.9b00723

Author

Tran, Kim Tai ; Pallesen, Jakob S ; Solbak, Sara Marie Øie ; Narayanan, Dilip ; Baig, Amina ; Zang, Jie ; Aguayo-Orozco, Alejandro ; Carmona, Rosa ; Garcia, Anthony ; Bach, Anders. / A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors : Chemical Synthesis, Binding Properties, and Cellular Activity. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 17. pp. 8028-8052.

Bibtex

@article{1ce635fa36c648b8be703481d3455f03,
title = "A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity",
abstract = "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.",
author = "Tran, {Kim Tai} and Pallesen, {Jakob S} and Solbak, {Sara Marie {\O}ie} and Dilip Narayanan and Amina Baig and Jie Zang and Alejandro Aguayo-Orozco and Rosa Carmona and Anthony Garcia and Anders Bach",
note = "- Covered by Derek Lowe at his {\textquoteleft}In the Pipeline{\textquoteright} blog https://blogs.sciencemag.org/pipeline/archives/2019/08/28/not-all-of-those-compounds-are-real-again",
year = "2019",
doi = "10.1021/acs.jmedchem.9b00723",
language = "English",
volume = "62",
pages = "8028--8052",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "17",

}

RIS

TY - JOUR

T1 - A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors

T2 - Chemical Synthesis, Binding Properties, and Cellular Activity

AU - Tran, Kim Tai

AU - Pallesen, Jakob S

AU - Solbak, Sara Marie Øie

AU - Narayanan, Dilip

AU - Baig, Amina

AU - Zang, Jie

AU - Aguayo-Orozco, Alejandro

AU - Carmona, Rosa

AU - Garcia, Anthony

AU - Bach, Anders

N1 - - Covered by Derek Lowe at his ‘In the Pipeline’ blog https://blogs.sciencemag.org/pipeline/archives/2019/08/28/not-all-of-those-compounds-are-real-again

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.9b00723

DO - 10.1021/acs.jmedchem.9b00723

M3 - Journal article

C2 - 31411465

VL - 62

SP - 8028

EP - 8052

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 17

ER -

ID: 225993575