title: 4-Biphenylalanine- and 3-Phenyltyrosine-Derived Hydroxamic Acids as Inhibitors of the JumonjiC-Domain-Containing Histone Demethylase KDM4A.
abstract: Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate-based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC50 value of 25.4 μm. Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low-micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs. Cell-permeable derivatives clearly showed a demethylase-inhibition-dependent antiproliferative effect against HL-60 human promyelocytic leukemia cells.
authors: Institute of Pharmaceutical Sciences, Albert Ludwigs University Freiburg, Albertstraße 25, 79104, Freiburg im Breisgau, Germany.
authors: Ludovica
authors: L
authors: Morera
authors: Institute of Pharmaceutical Sciences, Albert Ludwigs University Freiburg, Albertstraße 25, 79104, Freiburg im Breisgau, Germany.
authors: Martin
authors: M
authors: Roatsch
authors: Department of Chemistry and Pharmacy, Friedrich Alexander University ErlangenNuremberg, Schuhstraße 19, 91052, Erlangen, Germany.
authors: Michael C D
authors: MC
authors: Fürst
authors: Institute of Pharmaceutical Sciences, Albert Ludwigs University Freiburg, Albertstraße 25, 79104, Freiburg im Breisgau, Germany.
authors: Inga
authors: I
authors: Hoffmann
authors: Institute of Pharmaceutical Sciences, Albert Ludwigs University Freiburg, Albertstraße 25, 79104, Freiburg im Breisgau, Germany.
authors: Johanna
authors: J
authors: Senger
authors: Institute of Pharmaceutical Sciences, Albert Ludwigs University Freiburg, Albertstraße 25, 79104, Freiburg im Breisgau, Germany.
authors: Mirjam
authors: M
authors: Hau
authors: Central Clinical Research, University Medical Center Freiburg, Breisacher Straße 66, 79106, Freiburg im Breisgau, Germany.|Institute of Anatomy and Cell Biology, Albert Ludwigs University Freiburg, Albertstraße 17, 79104, Freiburg im Breisgau, Germany.
authors: Henriette
authors: H
authors: Franz
authors: Central Clinical Research, University Medical Center Freiburg, Breisacher Straße 66, 79106, Freiburg im Breisgau, Germany.
authors: Roland
authors: R
authors: Schüle
authors: Department of Chemistry and Pharmacy, Friedrich Alexander University ErlangenNuremberg, Schuhstraße 19, 91052, Erlangen, Germany.
authors: Markus R
authors: MR
authors: Heinrich
authors: Institute of Pharmaceutical Sciences, Albert Ludwigs University Freiburg, Albertstraße 25, 79104, Freiburg im Breisgau, Germany. manfred.jung@pharmazie.uni-freiburg.de.
authors: Manfred
authors: M
authors: Jung
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D006877:Hydroxamic Acids; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human
keywords: epigenetics; histone demethylase; inhibitors; medicinal chemistry; radical reactions