Small Molecule Inhibitors of 8-Oxoguanine DNA Glycosylase-1 (OGG1)

Published

August 7, 2015

Author(s)

Pawel Jaruga, Erdem Coskun, M Miral Dizdar, Nathan Donley, Stephen Lloyd, Amanda McCullough

Abstract

ABSTRACT The DNA base excision repair (BER) pathway, which utilizes DNA glycosylases to initiate repair of specific DNA lesions, is the major pathway for the repair of DNA damage induced by oxidation, alkylation, and deamination. Early results from clinical trials suggest that inhibiting certain enzymes in the BER pathway can be a useful anti-cancer strategy when combined with certain DNA-damaging agents or tumor-specific genetic deficiencies. Despite this general validation of BER enzymes as drug targets, there are many enzymes that function in the BER pathway that have few, if any, specific inhibitors. There is a growing body of evidence that suggests inhibition of 8-oxoguanine DNA glycosylase-1 (OGG1) could be useful as a mono-therapy or in combination therapy to treat certain types of cancer. To identify inhibitors of OGG1, a fluorescence-based screen was developed to analyze OGG1 activity in a high-throughput manner. From a primary screen of ≈50000 molecules, 13 inhibitors were identified, 12 of which were hydrazides or acyl hydrazones. Five inhibitors with an IC50 value of less than 1 μmol/L were chosen for further experimentation and verified using two additional biochemical assays. None of the five OGG1 inhibitors reduced DNA binding of OGG1 to a 7,8-dihydro-8-oxoguanine (8-oxo-Gua)‒containing substrate but all five inhibited Schiff base formation during OGG1-mediated catalysis. All of these inhibitors displayed a >100-fold selectivity for OGG1 relative to several other DNA glycosylases involved in repair of oxidatively-damaged bases. These inhibitors represent the most potent and selective OGG1 inhibitors identified to date.

Citation

ACS Chemical Biology

Volume

10

Pub Type

Journals

Download Paper

https://doi.org/10.1021/acschembio.5b00452

Keywords

OGG1, DNA glycosylases, BER, oxidative DNA damage, small molecule inhibitors, cancer therapy

Citation

Jaruga, P. , Coskun, E. , , M. , Donley, N. , Lloyd, S. and McCullough, A. (2015), Small Molecule Inhibitors of 8-Oxoguanine DNA Glycosylase-1 (OGG1), ACS Chemical Biology, [online], https://doi.org/10.1021/acschembio.5b00452 (Accessed April 19, 2024)