title: Diverse small molecule inhibitors of human apurinic/apyrimidinic endonuclease APE1 identified from a screen of a large public collection.
abstract: The major human apurinic/apyrimidinic endonuclease APE1 plays a pivotal role in the repair of base damage via participation in the DNA base excision repair (BER) pathway. Increased activity of APE1, often observed in tumor cells, is thought to contribute to resistance to various anticancer drugs, whereas down-regulation of APE1 sensitizes cells to DNA damaging agents. Thus, inhibiting APE1 repair endonuclease function in cancer cells is considered a promising strategy to overcome therapeutic agent resistance. Despite ongoing efforts, inhibitors of APE1 with adequate drug-like properties have yet to be discovered. Using a kinetic fluorescence assay, we conducted a fully-automated high-throughput screen (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR), as well as additional public collections, with each compound tested as a 7-concentration series in a 4 µL reaction volume. Actives identified from the screen were subjected to a panel of confirmatory and counterscreen tests. Several active molecules were identified that inhibited APE1 in two independent assay formats and exhibited potentiation of the genotoxic effect of methyl methanesulfonate with a concomitant increase in AP sites, a hallmark of intracellular APE1 inhibition; a number of these chemotypes could be good starting points for further medicinal chemistry optimization. To our knowledge, this represents the largest-scale HTS to identify inhibitors of APE1, and provides a key first step in the development of novel agents targeting BER for cancer treatment.
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Dorjbal
authors.initials: D
authors.lastname: Dorjsuren
authors.forename: Daemyung
authors.initials: D
authors.lastname: Kim
authors.forename: Vaddadi N
authors.initials: VN
authors.lastname: Vyjayanti
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
mesh_terms: D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008741:Methyl Methanesulfonate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015394:Molecular Structure; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D008741:Methyl Methanesulfonate; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase