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

Nathan Donley, Pawel Jaruga, Erdem Coskun, Miral Dizdaroglu, Amanda McCullough, Robert (Stephen) Lloyd

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 anticancer 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 monotherapy 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 ∼50 000 molecules, 13 inhibitors were identified, 12 of which were hydrazides or acyl hydrazones. Five inhibitors with an IC50 value of less than 1 μM 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.

Original languageEnglish (US)
Pages (from-to)2334-2343
Number of pages10
JournalACS Chemical Biology
Volume10
Issue number10
DOIs
StatePublished - Oct 16 2015

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DNA Glycosylases
Molecules
Repair
DNA Repair
DNA
Enzymes
8-hydroxyguanine
Hydrazones
Deamination
Schiff Bases
Alkylation
Catalysis
Inhibitory Concentration 50
DNA Damage
Tumors
Assays
Neoplasms
Fluorescence
Throughput
Clinical Trials

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Small Molecule Inhibitors of 8-Oxoguanine DNA Glycosylase-1 (OGG1). / Donley, Nathan; Jaruga, Pawel; Coskun, Erdem; Dizdaroglu, Miral; McCullough, Amanda; Lloyd, Robert (Stephen).

In: ACS Chemical Biology, Vol. 10, No. 10, 16.10.2015, p. 2334-2343.

Research output: Contribution to journalArticle

Donley, Nathan ; Jaruga, Pawel ; Coskun, Erdem ; Dizdaroglu, Miral ; McCullough, Amanda ; Lloyd, Robert (Stephen). / Small Molecule Inhibitors of 8-Oxoguanine DNA Glycosylase-1 (OGG1). In: ACS Chemical Biology. 2015 ; Vol. 10, No. 10. pp. 2334-2343.
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