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

Luca Sartori, Ciro Mercurio, Federica Amigoni, Anna Cappa, Giovanni Fagá, Raimondo Fattori, Elena Legnaghi, Giuseppe Ciossani, Andrea Mattevi, Giuseppe Meroni, Loris Moretti, Valentina Cecatiello, Sebastiano Pasqualato, Alessia Romussi, Florian Thaler, Paolo Trifiró, Manuela Villa, Stefania Vultaggio, Oronza A. Botrugno, Paola DessantiSaverio Minucci, Elisa Zagarrí, Daniele Carettoni, Lucia Iuzzolino, Mario Varasi, Paola Vianello

Research output: Contribution to journalArticle

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 IC50, 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, IC50 = 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 IC50 (0.162 μM), capable of inhibiting the target in cells.

Original languageEnglish
Pages (from-to)1673-1692
Number of pages20
JournalJournal of Medicinal Chemistry
Volume60
Issue number5
DOIs
Publication statusPublished - Mar 9 2017

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Sartori, L., Mercurio, C., Amigoni, F., Cappa, A., Fagá, G., Fattori, R., Legnaghi, E., Ciossani, G., Mattevi, A., Meroni, G., Moretti, L., Cecatiello, V., Pasqualato, S., Romussi, A., Thaler, F., Trifiró, P., Villa, M., Vultaggio, S., Botrugno, O. A., ... Vianello, P. (2017). 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. Journal of Medicinal Chemistry, 60(5), 1673-1692. https://doi.org/10.1021/acs.jmedchem.6b01018