6G40

Structure of the mouse 8-oxoguanine DNA Glycosylase mOGG1 in complex with ligand TH9525

Summary for 6G40

• Entry DOI: 10.2210/pdb6g40/pdb
• Descriptor: N-glycosylase/DNA lyase, ~{N}-(3-methoxy-4-methyl-phenyl)-4-(4-methoxy-2-oxidanylidene-3~{H}-benzimidazol-1-yl)piperidine-1-carboxamide, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• Functional Keywords: n-glycosylase, dna lyase, dna binding protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 3
• Total formula weight: 109082.34

Authors

Masuyer, G.,Helleday, T.,Stenmark, P. (deposition date: 2018-03-26, release date: 2019-04-10, Last modification date: 2024-02-07)

Primary citation

Wallner, O.,Cazares-Korner, A.,Scaletti, E.R.,Masuyer, G.,Bekkhus, T.,Visnes, T.,Mamonov, K.,Ortis, F.,Lundback, T.,Volkova, M.,Koolmeister, T.,Wiita, E.,Loseva, O.,Pandey, M.,Homan, E.,Benitez-Buelga, C.,Davies, J.,Scobie, M.,Warpman Berglund, U.,Kalderen, C.,Stenmark, P.,Helleday, T.,Michel, M.
Optimization of N-Piperidinyl-Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8-Oxo-Guanine DNA Glycosylase 1.
Chemmedchem, 18:e202200310-e202200310, 2023

PubMed 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.

PubMed: 36128847
DOI: 10.1002/cmdc.202200310

Experimental method

X-RAY DIFFRACTION (2.49 Å)