5LGN

Thieno[3,2-b]pyrrole-5-carboxamides as Novel Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1: Compound 19

Summary for 5LGN

• Entry DOI: 10.2210/pdb5lgn/pdb
• Descriptor: Lysine-specific histone demethylase 1A, REST corepressor 1, FLAVIN-ADENINE DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: oxidoreductase
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : O60341 Q9UKL0
• Total number of polymer chains: 2
• Total formula weight: 90988.63

Authors

Mattevi, A.,Ciossani, G. (deposition date: 2016-07-07, release date: 2017-02-22, Last modification date: 2024-01-10)

Primary citation

Sartori, L.,Mercurio, C.,Amigoni, F.,Cappa, A.,Faga, G.,Fattori, R.,Legnaghi, E.,Ciossani, G.,Mattevi, A.,Meroni, G.,Moretti, L.,Cecatiello, V.,Pasqualato, S.,Romussi, A.,Thaler, F.,Trifiro, P.,Villa, M.,Vultaggio, S.,Botrugno, O.A.,Dessanti, P.,Minucci, S.,Zagarri, E.,Carettoni, D.,Iuzzolino, L.,Varasi, M.,Vianello, P.
Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 1: High-Throughput Screening and Preliminary Exploration.
J. Med. Chem., 60:1673-1692, 2017

PubMed Abstract: Lysine specific demethylase 1 KDM1A (LSD1) regulates histone methylation and it is increasingly recognized as a potential therapeutic target in oncology. We report on a high-throughput screening campaign performed on KDM1A/CoREST, using a time-resolved fluorescence resonance energy transfer (TR-FRET) technology, to identify reversible inhibitors. The screening led to 115 hits for which we determined biochemical IC, thus identifying four chemical series. After data analysis, we have prioritized the chemical series of N-phenyl-4H-thieno[3, 2-b]pyrrole-5-carboxamide for which we obtained X-ray structures of the most potent hit (compound 19, IC = 2.9 μM) in complex with the enzyme. Initial expansion of this chemical class, both modifying core structure and decorating benzamide moiety, was directed toward the definition of the moieties responsible for the interaction with the enzyme. Preliminary optimization led to compound 90, which inhibited the enzyme with a submicromolar IC (0.162 μM), capable of inhibiting the target in cells.

PubMed: 28186755
DOI: 10.1021/acs.jmedchem.6b01018

Experimental method

X-RAY DIFFRACTION (3.2 Å)