title: Small Molecule Inhibitors of 8-Oxoguanine DNA Glycosylase-1 (OGG1).
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.
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University , Portland, Oregon 97239, United States.
authors.forename: Nathan
authors.initials: N
authors.lastname: Donley
authors.affiliation: Biomolecular Measurement Division, National Institute of Standards and Technology , Gaithersburg, Maryland 20899, United States.
authors.forename: Pawel
authors.initials: P
authors.lastname: Jaruga
authors.affiliation: Biomolecular Measurement Division, National Institute of Standards and Technology , Gaithersburg, Maryland 20899, United States.
authors.forename: Erdem
authors.initials: E
authors.lastname: Coskun
authors.affiliation: Biomolecular Measurement Division, National Institute of Standards and Technology , Gaithersburg, Maryland 20899, United States.
authors.forename: Miral
authors.initials: M
authors.lastname: Dizdaroglu
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University , Portland, Oregon 97239, United States.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: McCullough
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University , Portland, Oregon 97239, United States.
authors.forename: R Stephen
authors.initials: RS
authors.lastname: Lloyd
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045647:DNA Glycosylases / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000737:chemistry; D020128:Inhibitory Concentration 50; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006834:Hydrazines; D054852:Small Molecule Libraries; C029424:hydrazine; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human