title: Nonpeptidic propargylamines as inhibitors of lysine specific demethylase 1 (LSD1) with cellular activity.
abstract: Lysine demethylases play an important role in epigenetic regulation and thus in the development of diseases like cancer or neurodegenerative disorders. As the lysine specific demethylase 1 (LSD1/KDM1) has been strongly connected to androgen and estrogen dependent gene expression, it serves as a promising target for the therapy of hormone dependent cancer. Here, we report on the discovery of new small molecule inhibitors of LSD1 containing a propargylamine warhead, starting out from lysine containing substrate analogues. On the basis of these substrate mimicking inhibitors, we were able to increase potency by a combination of similarity-based virtual screening and subsequent synthetic optimization resulting in more druglike LSD1 inhibitors that led to histone hypermethylation in breast cancer cells.
authors.affiliation: Institute of Pharmaceutical Sciences, University of Freiburg , Albertstrasse 25, Freiburg 79104, Germany.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Schmitt
authors.forename: Alexander-Thomas
authors.initials: AT
authors.lastname: Hauser
authors.forename: Luca
authors.initials: L
authors.lastname: Carlino
authors.forename: Martin
authors.initials: M
authors.lastname: Pippel
authors.forename: Johannes
authors.initials: J
authors.lastname: Schulz-Fincke
authors.forename: Eric
authors.initials: E
authors.lastname: Metzger
authors.forename: Dominica
authors.initials: D
authors.lastname: Willmann
authors.forename: Teresa
authors.initials: T
authors.lastname: Yiu
authors.forename: Michelle
authors.initials: M
authors.lastname: Barton
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D062105:Molecular Docking Simulation; D011487:Protein Conformation
chemical_list: D000588:Amines; D004791:Enzyme Inhibitors; D006657:Histones; D056466:Histone Demethylases; C495195:KDM1A protein, human