ArticleChemMedChem2023
Optimization of N-Piperidinyl-Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8-Oxo-Guanine DNA Glycosylase 1.
Article in ChemMedChem, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
What it found
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Who cites it
7 citing papers in PubMed, 9 citations in OpenAlex.
- Parallels between the chloro and methoxy groups for potency optimization.RSC medicinal chemistry · 2026Article
- Nucleobase catalysts for the enzymatic activation of 8-oxoguanine DNA glycosylase 1.RSC chemical biology · 2026Article
- 8-Oxoguanine: A Lesion, an Epigenetic Mark, or a Molecular Signal?International journal of molecular sciences · 2025Review
- Organocatalytic Switches of DNA Glycosylase OGG1 Catalyze a Highly Efficient AP-Lyase Function.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Chemical Switching: A Concept Inspired by Strategies from Biocatalysis and Organocatalysis.Chembiochem : a European journal of chemical biology · 2025Review
- Virtual fragment screening for DNA repair inhibitors in vast chemical space.Nature communications · 2025Article
- Optimization of N-Piperidinyl-Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8-Oxo-Guanine DNA Glycosylase 1.ChemMedChem · 2023Article
Corrections and comments
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Authors and funding
23 authors at 3 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
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. 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.