The activity of DNA repair enzyme OGG1, which excises oxidized base 8-oxoguanine from DNA, is closely related to mutagenesis, genotoxicity, cancer, and inflammation. To investigate the roles of OGG1-mediated repair in these pathways, we have undertaken the development of noncovalent small-molecule inhibitors of the enzyme. Screening of library compounds using a recently developed fluorogenic 8-oxoguanine excision assay gave validated hit compounds, one of which was selected for further optimization. The structure-activity relationships of the hit compound were outlined by synthesizing a broad range of analogs. The optimized compound, SU0268, was shown to have low toxicity and was selective for inhibiting OGG1 over multiple repair enzymes, including other base excision repair enzymes.

Development of highly potent and selective inhibitors of DNA repair by 8-oxoguanine DNA glycosylase (OGG1)

255th National Meeting (2018)

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