Synthesis, biological activity and mechanistic insights of 1-substituted cyclopropylamine derivatives: A novel class of irreversible inhibitors of histone demethylase KDM1A

• DOI: 10.1016/j.ejmech.2014.08.068
• Publication Date: 2014-08-27T04:22:01Z
• Authors: Paola Vianello; Oronza A. Botrugno; Anna Cappa; Giuseppe Ciossani; Paola Dessanti; Antonello Mai; Andrea Mattevi; Giuseppe Meroni; Saverio Minucci; Florian Thaler; Marcello Tortorici; Paolo Trifiró; Sergio Valente; Manuela Villa; Mario Varasi; Ciro Mercurio
• Keywords: Cyclopropanes; Histone Demethylases; Models, Molecular; 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; Epigenetic; 610; 540; Crystallography, X-Ray; 3. Good health; Structure-Activity Relationship; 03 medical and health sciences; Humans; Enzyme Inhibitors; antitumor drugs; Monoamine Oxidase

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.