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Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2: Structure-Based Drug Design and Structure–Activity Relationship

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Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology, 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
# Genextra Group, DAC s.r.l., Via Adamello 16, 20139 Milano, Italy
*For P.V.: phone, +39 02 9437 5030; e-mail, [email protected]
*For L.S.: phone, +39 02 9437 5121; e-mail, [email protected]
Cite this: J. Med. Chem. 2017, 60, 5, 1693–1715
Publication Date (Web):February 10, 2017
Copyright © 2017 American Chemical Society

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    Abstract Image

    The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described (Part 1, DOI 10.1021.acs.jmedchem.6b01018) the identification of thieno[3,2-b]pyrrole-5-carboxamides as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series based on multiple ligand/KDM1A-CoRest cocrystal structures, which led to several extremely potent inhibitors. In particular, compounds 46, 49, and 50 showed single-digit nanomolar IC50 values for in vitro inhibition of KDM1A, with high selectivity in secondary assays. In THP-1 cells, these compounds transcriptionally affected the expression of genes regulated by KDM1A such as CD14, CD11b, and CD86. Moreover, 49 and 50 showed a remarkable anticlonogenic cell growth effect on MLL-AF9 human leukemia cells.

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b01019.

    • Synthetic procedures for the preparation of compounds 20e, 21e, 23e28e, and 44; material and methods for biochemical and cellular assays; data collection and refinement statistics for compounds 15, 17, 34, 49, and 50; HOMO values and localization; HOMO pictures for compounds 15, 2026, and 44; calculated physicochemical properties (molecular surface area, AlogP, and Log D) (PDF)

    • Molecular formula strings (CSV)

    • Protein Target (PDB)

    • Compound 2, pose A (PDB)

    • Compound 2, pose B (PDB)

    Accession Codes

    Atomic coordinates for the crystal structures of KDM1A with compounds 15, 17, 34, 49, and 50 can be accessed using PDB codes 5LGT, 5LHG, 5LGU, 5LHH, and 5LHI, respectively. Authors will release the atomic coordinates and experimental data upon article publication.

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