Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds

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

Standard

Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds. / Pallesen, Jakob S; Narayanan, Dilip; Tran, Kim T; Solbak, Sara M Ø; Marseglia, Giuseppe; Sørensen, Louis M E; Høj, Lars J; Munafò, Federico; Carmona, Rosa M C; Garcia, Anthony D; Desu, Haritha L; Brambilla, Roberta; Johansen, Tommy N; Popowicz, Grzegorz M; Sattler, Michael; Gajhede, Michael; Bach, Anders.

In: Journal of Medicinal Chemistry, Vol. 64, No. 8, 2021, p. 4623–4661.

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

Harvard

Pallesen, JS, Narayanan, D, Tran, KT, Solbak, SMØ, Marseglia, G, Sørensen, LME, Høj, LJ, Munafò, F, Carmona, RMC, Garcia, AD, Desu, HL, Brambilla, R, Johansen, TN, Popowicz, GM, Sattler, M, Gajhede, M & Bach, A 2021, 'Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds', Journal of Medicinal Chemistry, vol. 64, no. 8, pp. 4623–4661. https://doi.org/10.1021/acs.jmedchem.0c02094

APA

Pallesen, J. S., Narayanan, D., Tran, K. T., Solbak, S. M. Ø., Marseglia, G., Sørensen, L. M. E., Høj, L. J., Munafò, F., Carmona, R. M. C., Garcia, A. D., Desu, H. L., Brambilla, R., Johansen, T. N., Popowicz, G. M., Sattler, M., Gajhede, M., & Bach, A. (2021). Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds. Journal of Medicinal Chemistry, 64(8), 4623–4661. https://doi.org/10.1021/acs.jmedchem.0c02094

Vancouver

Pallesen JS, Narayanan D, Tran KT, Solbak SMØ, Marseglia G, Sørensen LME et al. Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds. Journal of Medicinal Chemistry. 2021;64(8):4623–4661. https://doi.org/10.1021/acs.jmedchem.0c02094

Author

Pallesen, Jakob S ; Narayanan, Dilip ; Tran, Kim T ; Solbak, Sara M Ø ; Marseglia, Giuseppe ; Sørensen, Louis M E ; Høj, Lars J ; Munafò, Federico ; Carmona, Rosa M C ; Garcia, Anthony D ; Desu, Haritha L ; Brambilla, Roberta ; Johansen, Tommy N ; Popowicz, Grzegorz M ; Sattler, Michael ; Gajhede, Michael ; Bach, Anders. / Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds. In: Journal of Medicinal Chemistry. 2021 ; Vol. 64, No. 8. pp. 4623–4661.

Bibtex

@article{926d690fa75b45a7a416f07b6f0c1ed4,
title = "Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds",
abstract = "Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.",
author = "Pallesen, {Jakob S} and Dilip Narayanan and Tran, {Kim T} and Solbak, {Sara M {\O}} and Giuseppe Marseglia and S{\o}rensen, {Louis M E} and H{\o}j, {Lars J} and Federico Munaf{\`o} and Carmona, {Rosa M C} and Garcia, {Anthony D} and Desu, {Haritha L} and Roberta Brambilla and Johansen, {Tommy N} and Popowicz, {Grzegorz M} and Michael Sattler and Michael Gajhede and Anders Bach",
year = "2021",
doi = "10.1021/acs.jmedchem.0c02094",
language = "English",
volume = "64",
pages = "4623–4661",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "8",

}

RIS

TY - JOUR

T1 - Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds

AU - Pallesen, Jakob S

AU - Narayanan, Dilip

AU - Tran, Kim T

AU - Solbak, Sara M Ø

AU - Marseglia, Giuseppe

AU - Sørensen, Louis M E

AU - Høj, Lars J

AU - Munafò, Federico

AU - Carmona, Rosa M C

AU - Garcia, Anthony D

AU - Desu, Haritha L

AU - Brambilla, Roberta

AU - Johansen, Tommy N

AU - Popowicz, Grzegorz M

AU - Sattler, Michael

AU - Gajhede, Michael

AU - Bach, Anders

PY - 2021

Y1 - 2021

N2 - Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.

AB - Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.

U2 - 10.1021/acs.jmedchem.0c02094

DO - 10.1021/acs.jmedchem.0c02094

M3 - Journal article

C2 - 33818106

VL - 64

SP - 4623

EP - 4661

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 8

ER -

ID: 259615125