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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 and Volkova, Maria , et al. (2023) In ChemMedChem 18(1).
Abstract

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.... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
8-oxo guanine DNA glycoslyase 1, Base excision repair, Inhibitors, OGG1, TH5487
in
ChemMedChem
volume
18
issue
1
publisher
Wiley-Blackwell
external identifiers
  • scopus:85139603319
  • pmid:36128847
ISSN
1860-7179
DOI
10.1002/cmdc.202200310
language
English
LU publication?
yes
id
7e1a37af-3ad4-459f-a6f1-7991a1a25a73
date added to LUP
2022-12-13 13:27:00
date last changed
2024-04-18 16:24:20
@article{7e1a37af-3ad4-459f-a6f1-7991a1a25a73,
  abstract     = {{<p>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.</p>}},
  author       = {{Wallner, Olov and Cázares-Körner, Armando and Scaletti, Emma Rose and Masuyer, Geoffrey and Bekkhus, Tove and Visnes, Torkild and Mamonov, Kirill and Ortis, Florian and Lundbäck, Thomas and Volkova, Maria and Koolmeister, Tobias and Wiita, Elisée and Loseva, Olga and Pandey, Monica and Homan, Evert and Benítez-Buelga, Carlos and Davies, Jonathan and Scobie, Martin and Warpman Berglund, Ulrika and Kalderén, Christina and Stenmark, Pål and Helleday, Thomas and Michel, Maurice}},
  issn         = {{1860-7179}},
  keywords     = {{8-oxo guanine DNA glycoslyase 1; Base excision repair; Inhibitors; OGG1; TH5487}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{ChemMedChem}},
  title        = {{Optimization of N-Piperidinyl-Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8-Oxo-Guanine DNA Glycosylase 1}},
  url          = {{http://dx.doi.org/10.1002/cmdc.202200310}},
  doi          = {{10.1002/cmdc.202200310}},
  volume       = {{18}},
  year         = {{2023}},
}