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

• Published in: European journal of medicinal chemistry 2015-03, Vol.92, p.377-386
• Main Authors: Pieroni, Marco, Annunziato, Giannamaria, Azzali, Elisa, Dessanti, Paola, Mercurio, Ciro, Meroni, Giuseppe, Trifiró, Paolo, Vianello, Paola, Villa, Manuela, Beato, Claudia, Varasi, Mario, Costantino, Gabriele
• Format: Article
• Language: English
• Subjects: Cyclopropanes - chemical synthesis; Cyclopropanes - chemistry; Cyclopropanes - pharmacology; Dose-Response Relationship, Drug; Epigenetic; Histone Demethylases - antagonists & inhibitors; Histone Demethylases - metabolism; Humans; Lysine demethylase; Models, Molecular; Molecular Structure; Recombinant Proteins - metabolism; Structure-Activity Relationship; Tranylcypromine
• ISSN: 0223-5234; 1768-3254
• DOI: 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. 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). [Display omitted] •We synthesized several TCPA derivatives variously substituted at the β-phenyl ring.•All of the compounds are endowed with high inhibitory activity toward KDM1.•The most active compounds bear halogens at the meta position of the β-phenyl ring.•The best compounds have low nanomolar activities (44a, 31 nM; 45a, 38 nM).•A computational model was built to rationalize the SAR data.