US EPA

7489392 

Journal Article 

Further insights into the SAR of α-substituted cyclopropylamine derivatives as inhibitors of histone demethylase KDM1A 

Pieroni, M; Annunziato, G; Azzali, E; Dessanti, P; Mercurio, C; Meroni, G; Trifirã³, P; Vianello, P; Villa, M; Beato, C; Varasi, M; Costantino, G 

2015 

Yes 

European Journal of Medicinal Chemistry
ISSN: 0223-5234
EISSN: 1768-3254 

Elsevier Masson SAS 

92 

377-386 

English 

10.1016/j.ejmech.2014.12.032 

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. Lysinespecific 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 1aee, 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). © 2015 Elsevier Masson SAS. All rights reserved. 

Epigenetic; Lysine demethylase; Tranylcypromine; 1 (ethoxycarbonyl) 2 phenylcyclopropanecarboxylic acid; 1 phenyl 4,7 diazaspiro[2.5]octan 8 one; 1 phenyl 7 oxa 4 azaspiro[2.5]octan 5 one; 1 [(tert butoxycarbonyl)amino] 2 phenylcyclopanecarboxylate; 2 bromo n [1 (hydroxymethyl) 2 phenylcyclopropyl]acetamide; 3 (4 chlorophenyl) 2 phenyl prop 2 enoic acid; antineoplastic agent; diethyl 2 benzylidenemalonate; diethyl 2 phenylcyclopropane 1,1 dicarboxylate; ethyl1 [[2 [(tert butoxycarbonyl)amino]ethyl]amino] 2 phenylcyclopropanecarboxylate; histone demethylase; oxygenase inhibitor; selegiline; tert butyl [1 (hydroxymethyl) 2 phenylcyclopropyl]carbamate; tranylcypromine derivative; unclassified drug; cyclopropane derivative; cyclopropylamine; KDM1A protein, human; recombinant protein; Article; controlled study; Curtius rearrangement; DNA methylation; enzyme active site; enzyme inhibition assay; epigenetics; histone acetylation; histone methylation; human; tumor cell line; antagonists and inhibitors; chemical structure; chemistry; dose response; metabolism; structure activity relation; synthesis; Cyclopropanes; Dose-Response Relationship, Drug; Histone Demethylases; Humans; Models, Molecular; Molecular Structure; Recombinant Proteins; Structure-Activity Relationship