Diverse small molecule inhibitors of human apurinic/apyrimidinic endonuclease APE1 identified from a screen of a large public collection

• Published in: PloS one 2012-10, Vol.7 (10), p.e47974
• Main Authors: Dorjsuren, Dorjbal, Kim, Daemyung, Vyjayanti, Vaddadi N, Maloney, David J, Jadhav, Ajit, Wilson, 3rd, David M, Simeonov, Anton
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic drugs; Antitumor agents; Apoptosis; Base excision repair; Biology; Cancer; Cancer therapies; Cancer treatment; Care and treatment; Cell cycle; Cell division; Cell Survival - drug effects; Cell Survival - genetics; Chemical compounds; Damage; Deoxyribonucleic acid; DNA; DNA Damage; DNA repair; DNA Repair - drug effects; DNA-(Apurinic or Apyrimidinic Site) Lyase - antagonists & inhibitors; DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism; Dosage and administration; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical - methods; Drug resistance; Drugs; Endonuclease; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fluorescence; Genomes; Genomics; Genotoxicity; Gerontology; Health aspects; HeLa Cells; Humans; Inhibitors; Laboratories; Medical screening; Medicine; Metabolites; Methyl methanesulfonate; Methyl Methanesulfonate - antagonists & inhibitors; Methyl Methanesulfonate - pharmacology; Molecular Structure; Nucleases; Optimization; Pharmacology; Potentiation; Proteins; Repair; Small Molecule Libraries; Structure-Activity Relationship; Tumor cells
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0047974

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.