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 studies to bind the enzyme both in the absence and in the presence of DNA. The compound SU0268 was shown to be selective for inhibiting OGG1 over multiple repair enzymes, including other base excision repair enzymes, and displayed no toxicity in two human cell lines at 10 μM. Finally, experiments confirm the ability of SU0268 to inhibit OGG1 in HeLa cells, resulting in an increase in accumulation of 8-OG in DNA. The results suggest the compound SU0268 as a potentially useful tool in studies of the role of OGG1 in multiple disease-related pathways.

Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights

“…Yet this situation is ideal in the case of a synthetic lethality interaction between the pathologic context and DNA glycosylase [58,59]. Over the last few years, the search for inhibitors of DNA glycosylases hNeil1 (hNeil2) and hOgg1 has become a very active field [18][19][20][21]56,60,61]. We started this research in 2014 by discovering that 2-thioxanthine is an irreversible inhibitor of the bacterial enzymes Fpg and Nei and the human enzyme hNeil2, three enzymes belonging to the Fpg/Nei DNA glycosylase structural superfamily having a zinc finger (ZnF) [18].…”

“…While recent studies have demonstrated the relevance of the research to design innovative anticancer strategies, only a few reported the search for hOgg1 and hNeil1 inhibitors [18][19][20][21]. In previous work, we initiated this study on DNA glycosylases from the structural Fpg/Nei superfamily [18,22,23].…”

Differential Repair Protein Recruitment at Sites of Clustered and Isolated DNA Double-Strand Breaks Produced by High-Energy Heavy Ions

“…Dosimetry was done using a Unidos dosemeter equipped with a soft X-ray ionisation chamber TM23342A (PTW, Freiburg, Germany) applying a correction factor (1.2) for the dose increase at the glass surface. For inhibition of BER pathway methoxyamine hydrochloride (20-35 mM) 59 , OGG1 inhibitor_O8 (50-75 µM) 60 and CRT0044876 (150-240 µM) 61 (all purchased from Sigma-Aldrich) were incubated with cells 1-2 h prior to irradiation as indicated.…”

Targeting BER enzymes in cancer therapy

“…Only recently these obstacles have been overcome for OGG1 by the development of a potent first in class compound series by Tahara et al [50]. However, it remains to be seen how these unusual nonpolar molecules behave in different cell lines and ADME studies.…”