title: Further insights into the SAR of α-substituted cyclopropylamine derivatives as inhibitors of histone demethylase KDM1A.
abstract: Epigenetics alterations including histone methylation and acetylation, and DNA methylation, are thought to play important roles in the onset and progression of cancer in numerous tumour cell lines. Lysine-specific demethylase 1 (LSD1 or KDM1A) is highly expressed in different cancer types and inhibiting KDM1A activity seems to have high therapeutic potential in cancer treatment. In the recent years, several inhibitors of KDM1A have been prepared and disclosed. The majority of these derivatives were designed based on the structure of tranylcypromine, as the cyclopropane core is responsible for the covalent interaction between the inhibitor and the catalytic domain of KDM proteins. In this study, we have further extended the SAR regarding compounds 1a-e, which were recently found to inhibit KDM1A with good activity. The decoration of the phenyl ring at the β-position of the cyclopropane ring with small functional groups, mostly halogenated, and in particular at the meta position, led to a significant improvement of the inhibitory activity against KDM1A, as exemplified by compound 44a, which has a potency in the low nanomolar range (31 nM).
authors.affiliation: Dipartimento Farmaceutico, University of Parma, Parco Area delle Scienze 27/A, Parma 43124, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pieroni
authors.affiliation: Dipartimento Farmaceutico, University of Parma, Parco Area delle Scienze 27/A, Parma 43124, Italy.
authors.forename: Giannamaria
authors.initials: G
authors.lastname: Annunziato
authors.affiliation: Dipartimento Farmaceutico, University of Parma, Parco Area delle Scienze 27/A, Parma 43124, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Azzali
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: Drug Discovery Unit, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
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.
authors.forename: Paolo
authors.initials: P
authors.lastname: Trifiró
authors.affiliation: Drug Discovery Unit, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
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: Manuela
authors.initials: M
authors.lastname: Villa
authors.affiliation: Dipartimento Farmaceutico, University of Parma, Parco Area delle Scienze 27/A, Parma 43124, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Beato
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: Dipartimento Farmaceutico, University of Parma, Parco Area delle Scienze 27/A, Parma 43124, Italy. Electronic address: gabriele.costantino@unipr.it.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
mesh_terms: D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D003521:Cyclopropanes; D011994:Recombinant Proteins; C067351:cyclopropylamine; D056466:Histone Demethylases; C495195:KDM1A protein, human
keywords: Epigenetic; Lysine demethylase; Tranylcypromine