4UVB

LSD1(KDM1A)-CoREST in complex with 1-Methyl-Tranylcypromine (1S,2R)

Summary for 4UVB

• Entry DOI: 10.2210/pdb4uvb/pdb
• Related: 4UV8 4UV9 4UVA 4UVC
• Descriptor: LYSINE-SPECIFIC HISTONE DEMETHYLASE 1A, REST COREPRESSOR 1, [(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl (2R,3S,4S)-5-[(1R,3S,3aS,7aS)-1-amino-1,10,11-trimethyl-4,6-dioxo-3-phenyl-2,3,5,6,7,7a-hexahydro-1H-benzo[g]pyrrolo[2,1-e]pteridin-8(4H)-yl]-2,3,4-trihydroxypentyl dihydrogen diphosphate (3 entities in total)
• Functional Keywords: transcription, covalent inhibitor
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Nucleus: O60341 Q9UKL0
• Total number of polymer chains: 2
• Total formula weight: 148882.98

Authors

Vianello, P.,Botrugno, O.,Cappa, A.,Ciossani, G.,Dessanti, P.,Mai, A.,Mattevi, A.,Meroni, G.,Minucci, S.,Thaler, F.,Tortorici, M.,Trifiro, P.,Valente, S.,Villa, M.,Varasi, M.,Mercurio, C. (deposition date: 2014-08-05, release date: 2014-09-10, Last modification date: 2024-01-10)

Primary citation

Vianello, P.,Botrugno, O.A.,Cappa, A.,Ciossani, G.,Dessanti, P.,Mai, A.,Mattevi, A.,Meroni, G.,Minucci, S.,Thaler, F.,Tortorici, M.,Trifiro, P.,Valente, S.,Villa, M.,Varasi, M.,Mercurio, C.
Synthesis, Biological Activity and Mechanistic Insights of 1-Substituted Cyclopropylamine Derivatives: A Novel Class of Irreversible Inhibitors of Histone Demethylase Kdm1A.
Eur.J.Med.Chem., 86C:352-, 2014

PubMed 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.

PubMed: 25173853
DOI: 10.1016/J.EJMECH.2014.08.068

Experimental method

X-RAY DIFFRACTION (2.8 Å)