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Optimization of N‐Piperidinyl‐Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8‐Oxo‐Guanine DNA Glycosylase 1
8‐oxo Guanine DNA Glycosylase 1 is the initiating enzyme within base excision repair and removes oxidized guanines from damaged DNA. Since unrepaired 8‐oxoG could lead to G : C→T : A transversion, base removal is of utmost importance for cells to ensure genomic integrity. For cells with elevated lev...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10092094/ https://www.ncbi.nlm.nih.gov/pubmed/36128847 http://dx.doi.org/10.1002/cmdc.202200310 |
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author | Wallner, Olov Cázares‐Körner, Armando Scaletti, Emma Rose Masuyer, Geoffrey Bekkhus, Tove Visnes, Torkild Mamonov, Kirill Ortis, Florian Lundbäck, Thomas Volkova, Maria Koolmeister, Tobias Wiita, Elisée Loseva, Olga Pandey, Monica Homan, Evert Benítez‐Buelga, Carlos Davies, Jonathan Scobie, Martin Warpman Berglund, Ulrika Kalderén, Christina Stenmark, Pål Helleday, Thomas Michel, Maurice |
author_facet | Wallner, Olov Cázares‐Körner, Armando Scaletti, Emma Rose Masuyer, Geoffrey Bekkhus, Tove Visnes, Torkild Mamonov, Kirill Ortis, Florian Lundbäck, Thomas Volkova, Maria Koolmeister, Tobias Wiita, Elisée Loseva, Olga Pandey, Monica Homan, Evert Benítez‐Buelga, Carlos Davies, Jonathan Scobie, Martin Warpman Berglund, Ulrika Kalderén, Christina Stenmark, Pål Helleday, Thomas Michel, Maurice |
author_sort | Wallner, Olov |
collection | PubMed |
description | 8‐oxo Guanine DNA Glycosylase 1 is the initiating enzyme within base excision repair and removes oxidized guanines from damaged DNA. Since unrepaired 8‐oxoG could lead to G : C→T : A transversion, base removal is of utmost importance for cells to ensure genomic integrity. For cells with elevated levels of reactive oxygen species this dependency is further increased. In the past we and others have validated OGG1 as a target for inhibitors to treat cancer and inflammation. Here, we present the optimization campaign that led to the broadly used tool compound TH5487. Based on results from a small molecule screening campaign, we performed hit to lead expansion and arrived at potent and selective substituted N‐piperidinyl‐benzimidazolones. Using X‐ray crystallography data, we describe the surprising binding mode of the most potent member of the class, TH8535. Here, the N‐Piperidinyl‐linker adopts a chair instead of a boat conformation which was found for weaker analogues. We further demonstrate cellular target engagement and efficacy of TH8535 against a number of cancer cell lines. |
format | Online Article Text |
id | pubmed-10092094 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-100920942023-04-13 Optimization of N‐Piperidinyl‐Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8‐Oxo‐Guanine DNA Glycosylase 1 Wallner, Olov Cázares‐Körner, Armando Scaletti, Emma Rose Masuyer, Geoffrey Bekkhus, Tove Visnes, Torkild Mamonov, Kirill Ortis, Florian Lundbäck, Thomas Volkova, Maria Koolmeister, Tobias Wiita, Elisée Loseva, Olga Pandey, Monica Homan, Evert Benítez‐Buelga, Carlos Davies, Jonathan Scobie, Martin Warpman Berglund, Ulrika Kalderén, Christina Stenmark, Pål Helleday, Thomas Michel, Maurice ChemMedChem Research Articles 8‐oxo Guanine DNA Glycosylase 1 is the initiating enzyme within base excision repair and removes oxidized guanines from damaged DNA. Since unrepaired 8‐oxoG could lead to G : C→T : A transversion, base removal is of utmost importance for cells to ensure genomic integrity. For cells with elevated levels of reactive oxygen species this dependency is further increased. In the past we and others have validated OGG1 as a target for inhibitors to treat cancer and inflammation. Here, we present the optimization campaign that led to the broadly used tool compound TH5487. Based on results from a small molecule screening campaign, we performed hit to lead expansion and arrived at potent and selective substituted N‐piperidinyl‐benzimidazolones. Using X‐ray crystallography data, we describe the surprising binding mode of the most potent member of the class, TH8535. Here, the N‐Piperidinyl‐linker adopts a chair instead of a boat conformation which was found for weaker analogues. We further demonstrate cellular target engagement and efficacy of TH8535 against a number of cancer cell lines. John Wiley and Sons Inc. 2022-10-13 2023-01-03 /pmc/articles/PMC10092094/ /pubmed/36128847 http://dx.doi.org/10.1002/cmdc.202200310 Text en © 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Wallner, Olov Cázares‐Körner, Armando Scaletti, Emma Rose Masuyer, Geoffrey Bekkhus, Tove Visnes, Torkild Mamonov, Kirill Ortis, Florian Lundbäck, Thomas Volkova, Maria Koolmeister, Tobias Wiita, Elisée Loseva, Olga Pandey, Monica Homan, Evert Benítez‐Buelga, Carlos Davies, Jonathan Scobie, Martin Warpman Berglund, Ulrika Kalderén, Christina Stenmark, Pål Helleday, Thomas Michel, Maurice Optimization of N‐Piperidinyl‐Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8‐Oxo‐Guanine DNA Glycosylase 1 |
title | Optimization of N‐Piperidinyl‐Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8‐Oxo‐Guanine DNA Glycosylase 1 |
title_full | Optimization of N‐Piperidinyl‐Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8‐Oxo‐Guanine DNA Glycosylase 1 |
title_fullStr | Optimization of N‐Piperidinyl‐Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8‐Oxo‐Guanine DNA Glycosylase 1 |
title_full_unstemmed | Optimization of N‐Piperidinyl‐Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8‐Oxo‐Guanine DNA Glycosylase 1 |
title_short | Optimization of N‐Piperidinyl‐Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8‐Oxo‐Guanine DNA Glycosylase 1 |
title_sort | optimization of n‐piperidinyl‐benzimidazolone derivatives as potent and selective inhibitors of 8‐oxo‐guanine dna glycosylase 1 |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10092094/ https://www.ncbi.nlm.nih.gov/pubmed/36128847 http://dx.doi.org/10.1002/cmdc.202200310 |
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