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J Med Chem. 2017 Mar 9;60(5):1673-1692. doi: 10.1021/acs.jmedchem.6b01018. Epub 2017 Feb 27.

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.

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Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
Genextra Group, DAC s.r.l. , Via Adamello 16, 20139 Milano, Italy.
Department of Biology and Biotechnology, University of Pavia , Via Ferrata 1, 27100 Pavia, Italy.
Crystallography Unit, Department of Experimental Oncology, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
IFOM- The FIRC Institute of Molecular Oncology Foundation , Via Adamello 16, 20139 Milano, Italy.
Department of Biosciences, University of Milan , Via Celoria, 26, 20133 Milano, Italy.
Axxam , via A. Meucci 3, 20091 Bresso, Milano, Italy.


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.

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