Diverse small molecule inhibitors of human apurinic/apyrimidinic endonuclease APE1 identified from a screen of a large public collection
| Autor: | Anton Simeonov, Daemyung Kim, Vaddadi N. Vyjayanti, David J. Maloney, David M. Wilson, Ajit Jadhav, Dorjbal Dorjsuren |
|---|---|
| Přispěvatelé: | Woloschak, Gayle E |
| Rok vydání: | 2012 |
| Předmět: |
DNA Repair
Cancer Treatment Drug Evaluation Preclinical lcsh:Medicine Biochemistry Endonuclease chemistry.chemical_compound Drug Discovery Basic Cancer Research DNA-(Apurinic or Apyrimidinic Site) Lyase Enzyme Inhibitors lcsh:Science Cancer Multidisciplinary biology Molecular Structure Small molecule Preclinical Nucleic acids Oncology 5.1 Pharmaceuticals Medicine Drug Development of treatments and therapeutic interventions Research Article Biotechnology DNA damage DNA repair Cell Survival General Science & Technology Dose-Response Relationship Small Molecule Libraries Structure-Activity Relationship DNA-binding proteins Chemical Biology Humans AP site Biology Dose-Response Relationship Drug lcsh:R Proteins DNA Methyl Methanesulfonate Molecular biology Methyl methanesulfonate chemistry Small Molecules Hela Cells Cancer cell biology.protein Drug Evaluation lcsh:Q HeLa Cells DNA Damage |
| Zdroj: | PloS one, vol 7, iss 10 PLoS ONE, Vol 7, Iss 10, p e47974 (2012) PLoS ONE |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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