title: Substituted 2-(2-aminopyrimidin-4-yl)pyridine-4-carboxylates as potent inhibitors of JumonjiC domain-containing histone demethylases.
abstract: Aberrant expression of iron(II)- and 2-oxoglutarate-dependent JumonjiC histone demethylases has been linked to cancer. Potent demethylase inhibitors are drug candidates and biochemical tools to elucidate the functional impact of demethylase inhibition.
  
  
  
  Virtual screening identified a novel lead scaffold against JMJD2A with low-micromolar potency in vitro. Analogs were acquired from commercial sources respectively synthesized in feedback with biological testing. Optimized compounds were transformed into cell-permeable prodrugs. A cocrystal x-ray structure revealed the mode of binding of these compounds as competitive to 2-oxoglutarate and confirmed kinetic experiments. Selectivity studies revealed a preference for JMJD2A and JARID1A over JMJD3.
  
  
  
  Virtual screening and rational structural optimization led to a novel scaffold for highly potent and selective JMJD2A inhibitors.
authors.affiliation: Albert-Ludwigs-University Freiburg, Institute of Pharmaceutical Sciences, Albertstraße 25, 79104 Freiburg i.Br., Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Roatsch
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Institute of Pharmacy, Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.
authors.forename: Dina
authors.initials: D
authors.lastname: Robaa
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Institute of Pharmacy, Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Pippel
authors.affiliation: Oxford Protein Production Facility UK (OPPF-UK), Rutherford Appleton Laboratory, Harwell Science & Innovation Campus, Didcot, Oxfordshire, OX11 0FA, UK.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Nettleship
authors.affiliation: Oxford Protein Production Facility UK (OPPF-UK), Rutherford Appleton Laboratory, Harwell Science & Innovation Campus, Didcot, Oxfordshire, OX11 0FA, UK.
authors.forename: Yamini
authors.initials: Y
authors.lastname: Reddivari
authors.affiliation: Oxford Protein Production Facility UK (OPPF-UK), Rutherford Appleton Laboratory, Harwell Science & Innovation Campus, Didcot, Oxfordshire, OX11 0FA, UK.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Bird
authors.affiliation: Albert-Ludwigs-University Freiburg, Institute of Pharmaceutical Sciences, Albertstraße 25, 79104 Freiburg i.Br., Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Hoffmann
authors.affiliation: University Medical Center Freiburg, Central Clinical Research, Breisacher Straße 66, 79106 Freiburg i.Br., Germany.
authors.forename: Henriette
authors.initials: H
authors.lastname: Franz
authors.affiliation: Oxford Protein Production Facility UK (OPPF-UK), Rutherford Appleton Laboratory, Harwell Science & Innovation Campus, Didcot, Oxfordshire, OX11 0FA, UK.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Owens
authors.affiliation: University Medical Center Freiburg, Central Clinical Research, Breisacher Straße 66, 79106 Freiburg i.Br., Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
authors.affiliation: Diamond Light Source, Harwell Science & Innovation Campus, Didcot, Oxfordshire, OX11 0DE, UK.
authors.forename: Ralf
authors.initials: R
authors.lastname: Flaig
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Institute of Pharmacy, Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.affiliation: Albert-Ludwigs-University Freiburg, Institute of Pharmaceutical Sciences, Albertstraße 25, 79104 Freiburg i.Br., Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007539:Isonicotinic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D056572:Histone Deacetylase Inhibitors; D007539:Isonicotinic Acids; D011355:Prodrugs; D011743:Pyrimidines; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human
keywords: JumonjiC domain; aminopyrimidylpyridines; epigenetics; histone demethylase; metal chelators; prodrugs; virtual screening