title: Synthesis, biological activity and mechanistic insights of 1-substituted cyclopropylamine derivatives: a novel class of irreversible inhibitors of histone demethylase KDM1A.
abstract: Histone demethylase KDM1A (also known as LSD1) has become an attractive therapeutic target for the treatment of cancer as well as other disorders such as viral infections. We report on the synthesis of compounds derived from the expansion of tranylcypromine as a chemical scaffold for the design of novel demethylase inhibitors. These compounds, which are substituted on the cyclopropyl core moiety, were evaluated for their ability to inhibit KDM1A in vitro as well as to function in cells by modulating the expression of Gfi-1b, a well recognized KDM1A target gene. The molecules were all found to covalently inhibit KDM1A and to become increasingly selective against human monoamine oxidases MAO A and MAO B through the introduction of bulkier substituents on the cyclopropylamine ring. Structural and biochemical analysis of selected trans isomers showed that the two stereoisomers are endowed with similar inhibitory activities against KDM1A, but form different covalent adducts with the FAD co-enzyme.
authors.affiliation: Drug Discovery Unit, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy. Electronic address: paola.vianello@ieo.eu.
authors.forename: Paola
authors.initials: P
authors.lastname: Vianello
authors.affiliation: Drug Discovery Unit, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Oronza A
authors.initials: OA
authors.lastname: Botrugno
authors.affiliation: Drug Discovery Unit, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Cappa
authors.affiliation: Department of Biology and Biotechnology, University of Pavia, Via Ferrata 1, 27100 Pavia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ciossani
authors.affiliation: Drug Discovery Unit, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Dessanti
authors.affiliation: Pasteur Institute - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, University "La Sapienza", P.le A. Moro 5, 00185 Roma, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.affiliation: Department of Biology and Biotechnology, University of Pavia, Via Ferrata 1, 27100 Pavia, Italy. Electronic address: andrea.mattevi@unipv.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattevi
authors.affiliation: Drug Discovery Unit, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Meroni
authors.affiliation: Drug Discovery Unit, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy; Department of Biosciences, University of Milan, Via Celoria, 26, 20133 Milan, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.affiliation: Drug Discovery Unit, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy. Electronic address: florian.thaler@ieo.eu.
authors.forename: Florian
authors.initials: F
authors.lastname: Thaler
authors.affiliation: Department of Biology and Biotechnology, University of Pavia, Via Ferrata 1, 27100 Pavia, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Tortorici
authors.affiliation: Drug Discovery Unit, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Trifiró
authors.affiliation: Pasteur Institute - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, University "La Sapienza", P.le A. Moro 5, 00185 Roma, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Valente
authors.affiliation: Drug Discovery Unit, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Villa
authors.affiliation: Drug Discovery Unit, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.affiliation: Drug Discovery Unit, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
mesh_terms: D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D003521:Cyclopropanes; D004791:Enzyme Inhibitors; C067351:cyclopropylamine; D056466:Histone Demethylases; D008995:Monoamine Oxidase; C495195:KDM1A protein, human
keywords: Antiproliferation; Epigenetics; Histone lysine demethylases; Tranylcypromine; X-ray crystallography