The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. 8-Oxoguanine DNA glycosylase 1 (OGG1) binds with high affinity to 8-oxoG in double-stranded DNA to initiate DNA base excision repair. TH5487, a potent and selective OGG1 inhibitor with an IC50 of 342 nM, hampers OGG1 binding to and repair of 8-oxoG. The amount of OGG1-DNA complexes decreased in a dose-dependent manner upon addition of TH5487, demonstrating that TH5487 precludes OGG1 from binding oxidized DNA in vitro. TH5487 (10 μM) increased the melting temperature of OGG1 in Jurkat A3 cells, demonstrating that TH5487 protected it from thermal denaturation. Further, treatment with 5 μM TH5487 decreased CXCL1 (a proinflammatory gene) expression by >50% in human embryonic kidney (HEK) 293T cells suggesting TH5487 can specifically inhibit OGG1-dependent proinflammatory gene expression. Crucially, TH5487 decreased TNFα- and LPS-induced gene expression in diploid human small-airway epithelial cells (hSAECs) as well. In vivo, TNFα (20 ng/ml) robustly induced the expression of pulmonary proinflammatory genes in mice, but a prophylactic injection of TH5487 (30 mg/kg) decreased the expression levels[1].
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