title: Inhibitors of the apurinic/apyrimidinic endonuclease 1 (APE1)/nucleophosmin (NPM1) interaction that display anti-tumor properties.
abstract: The apurinic/apyrimidinic endonuclease 1 (APE1) is a protein central to the base excision DNA repair pathway and operates in the modulation of gene expression through redox-dependent and independent mechanisms. Aberrant expression and localization of APE1 in tumors are recurrent hallmarks of aggressiveness and resistance to therapy. We identified and characterized the molecular association between APE1 and nucleophosmin (NPM1), a multifunctional protein involved in the preservation of genome stability and rRNA maturation. This protein-protein interaction modulates subcellular localization and endonuclease activity of APE1. Moreover, we reported a correlation between APE1 and NPM1 expression levels in ovarian cancer, with NPM1 overexpression being a marker of poor prognosis. These observations suggest that tumors that display an augmented APE1/NPM1 association may exhibit increased aggressiveness and resistance. Therefore, targeting the APE1/NPM1 interaction might represent an innovative strategy for the development of anticancer drugs, as tumor cells relying on higher levels of APE1 and NPM1 for proliferation and survival may be more sensitive than untransformed cells. We set up a chemiluminescence-based high-throughput screening assay in order to find small molecules able to interfere with the APE1/NPM1 interaction. This screening led to the identification of a set of bioactive compounds that impair the APE1/NPM1 association in living cells. Interestingly, some of these molecules display anti-proliferative activity and sensitize cells to therapeutically relevant genotoxins. Given the prognostic significance of APE1 and NPM1, these compounds might prove effective in the treatment of tumors that show abundant levels of both proteins, such as ovarian or hepatic carcinomas.
authors: Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
authors: Mattia
authors: M
authors: Poletto
authors: Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
authors: Matilde C
authors: MC
authors: Malfatti
authors: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland.
authors: Dorjbal
authors: D
authors: Dorjsuren
authors: Department of Pharmacy, CIRPEB (Centro Interuniversitario di Ricerca sui Peptidi Bioattivi), University of Naples 'Federico II', Naples, Italy.|Center for Advanced Biomaterials for Healthcare@CRIB, Istituto Italiano di Tecnologia (IIT), Naples, Italy.
authors: Pasqualina L
authors: PL
authors: Scognamiglio
authors: Department of Pharmacy, CIRPEB (Centro Interuniversitario di Ricerca sui Peptidi Bioattivi), University of Naples 'Federico II', Naples, Italy.
authors: Daniela
authors: D
authors: Marasco
authors: Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
authors: Carlo
authors: C
authors: Vascotto
authors: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland.
authors: Ajit
authors: A
authors: Jadhav
authors: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland.
authors: David J
authors: DJ
authors: Maloney
authors: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
authors: David M
authors: DM
authors: Wilson
authors: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland.
authors: Anton
authors: A
authors: Simeonov
authors: Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
authors: Gianluca
authors: G
authors: Tell
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D061986:MCF-7 Cells; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000090243:Nucleophosmin; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D054852:Small Molecule Libraries; D000090243:Nucleophosmin; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: APE1; NPM1; combination therapy; protein/protein interaction; small molecule