title: Fluorinated tranylcypromine analogues as inhibitors of lysine-specific demethylase 1 (LSD1, KDM1A).
abstract: We report a series of tranylcypromine analogues containing a fluorine in the cyclopropyl ring. A number of compounds with additional m- or p-substitution of the aryl ring were micromolar inhibitors of the LSD1 enzyme. In cellular assays, the compounds inhibited the proliferation of acute myeloid leukemia cell lines. Increased levels of the biomarkers H3K4me2 and CD86 were consistent with LSD1 target engagement.
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Borrello
authors.affiliation: Organisch-Chemisches Institut, Universität Münster, Corrensstraβe 40, Germany; Cells-in-Motion, Cluster of Excellence, University of Münster, Waldeyerstraβe 15, 48149 Münster, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schinor
authors.affiliation: Organisch-Chemisches Institut, Universität Münster, Corrensstraβe 40, Germany; Cells-in-Motion, Cluster of Excellence, University of Münster, Waldeyerstraβe 15, 48149 Münster, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Bartels
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom.
authors.forename: Hanae
authors.initials: H
authors.lastname: Benelkebir
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Pereira
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom.
authors.forename: Wafa T
authors.initials: WT
authors.lastname: Al-Jamal
authors.affiliation: Cancer Research UK Centre, University of Southampton, University Road, SO17 1BJ Southampton, United Kingdom.
authors.forename: Leon
authors.initials: L
authors.lastname: Douglas
authors.affiliation: Cancer Research UK Centre, University of Southampton, University Road, SO17 1BJ Southampton, United Kingdom.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Duriez
authors.affiliation: Cancer Research UK Centre, University of Southampton, University Road, SO17 1BJ Southampton, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
authors.affiliation: Organisch-Chemisches Institut, Universität Münster, Corrensstraβe 40, Germany; Cells-in-Motion, Cluster of Excellence, University of Münster, Waldeyerstraβe 15, 48149 Münster, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Haufe
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom. Electronic address: a.ganesan@uea.ac.uk.
authors.forename: A
authors.initials: A
authors.lastname: Ganesan
mesh_terms: D051940:B7-2 Antigen / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D054879:Halogenation; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D014191:Tranylcypromine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity
chemical_list: D051940:B7-2 Antigen; D015415:Biomarkers; D004791:Enzyme Inhibitors; D006657:Histones; D014191:Tranylcypromine; D056466:Histone Demethylases; C495195:KDM1A protein, human
keywords: Epigenetics; FAD-dependent enzymes; Lysine demethylase; Mechanism based inhibitors; Organofluorine compounds