title: Identification of a Novel Benzimidazole Pyrazolone Scaffold That Inhibits KDM4 Lysine Demethylases and Reduces Proliferation of Prostate Cancer Cells.
abstract: Human lysine demethylase (KDM) enzymes (KDM1-7) constitute an emerging class of therapeutic targets, with activities that support growth and development of metastatic disease. By interacting with and co-activating the androgen receptor, the KDM4 subfamily (KDM4A-E) promotes aggressive phenotypes of prostate cancer (PCa). Knockdown of KDM4 expression or inhibition of KDM4 enzyme activity reduces the proliferation of PCa cell lines and highlights inhibition of lysine demethylation as a possible therapeutic method for PCa treatment. To address this possibility, we screened the ChemBioNet small molecule library for inhibitors of the human KDM4E isoform and identified several compounds with IC50values in the low micromolar range. Two hits, validated as active by an orthogonal enzyme-linked immunosorbent assay, displayed moderate selectivity toward the KDM4 subfamily and exhibited antiproliferative effects in cellular models of PCa. These compounds were further characterized by their ability to maintain the transcriptionally silent histone H3 tri-methyl K9 epigenetic mark at subcytotoxic concentrations. Taken together, these efforts identify and validate a hydroxyquinoline scaffold and a novel benzimidazole pyrazolone scaffold as tractable for entry into hit-to-lead chemical optimization campaigns.
authors.affiliation: 1 Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: David M
authors.initials: DM
authors.lastname: Carter
authors.affiliation: 2 Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Specker
authors.affiliation: 1 Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.|2 Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Przygodda
authors.affiliation: 2 Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Neuenschwander
authors.affiliation: 2 Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Jens Peter
authors.initials: JP
authors.lastname: von Kries
authors.affiliation: 1 Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Heinemann
authors.affiliation: 2 Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Nazaré
authors.affiliation: 1 Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Gohlke
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000073398:Demethylation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056466:Histone Demethylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors*; D008239:Lysine / Q000037:antagonists & inhibitors*; D008297:Male; D000078722:PC-3 Cells; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047069:Pyrazolones / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D006657:Histones; D006912:Hydroxyquinolines; D047069:Pyrazolones; D011944:Receptors, Androgen; C038362:pyrazolone; C031000:benzimidazole; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human; D008239:Lysine
keywords: cancer; epigenetics; high-throughput screening (HTS); lysine demethylase (KDM)