Potent and Selective Inhibitors of 8-Oxoguanine DNA Glycosylase.

ABSTRACT: The activity of DNA repair enzyme 8-oxoguanine DNA glycosylase (OGG1), which excises oxidized base 8-oxoguanine (8-OG) from DNA, is closely linked to mutagenesis, genotoxicity, cancer, and inflammation. To test the roles of OGG1-mediated repair in these pathways, we have undertaken the development of noncovalent small-molecule inhibitors of the enzyme. Screening of a PubChem-annotated library using a recently developed fluorogenic 8-OG excision assay resulted in multiple validated hit structures, including selected lead hit tetrahydroquinoline 1 (IC₅₀ = 1.7 μM). Optimization of the tetrahydroquinoline scaffold over five regions of the structure ultimately yielded amidobiphenyl compound 41 (SU0268; IC₅₀ = 0.059 μM). SU0268 was confirmed by surface plasmon resonance stu

SUBMITTER: Tahara YK 

PROVIDER: S-EPMC5823510 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature