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Issue 11, 2013
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Development and evaluation of selective, reversible LSD1 inhibitors derived from fragments

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Abstract

Two series of aminothiazoles have been developed as reversible inhibitors of lysine specific demethylase 1 (LSD1) through the expansion of a hit derived from a high concentration biochemical fragment based screen of 2466 compounds. The potency of the initial fragment hit was increased 32-fold through synthesis, with one series of compounds showing clear structure–activity relationships and inhibitory activities in the range of 7 to 187 μM in a biochemical assay. This series also showed selectivity against the related FAD-dependent enzyme mono-amine oxidase A (MAO-A). Although a wide range of irreversible inhibitors of LSD1 have been reported with activities in the low nanomolar range, this work represents one of the first reported examples of a reversible small molecule inhibitor of LSD1 with clear SAR and selectivity against MAO-A, and could provide a platform for the development of more potent reversible inhibitors. Herein, we also report the use of a recently developed cell-based assay for profiling LSD1 inhibitors, and present results on our own compounds as well as a selection of recently described reversible LSD1 inhibitors.

Graphical abstract: Development and evaluation of selective, reversible LSD1 inhibitors derived from fragments

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Publication details

The article was received on 06 Aug 2013, accepted on 28 Sep 2013 and first published on 02 Oct 2013


Article type: Concise Article
DOI: 10.1039/C3MD00226H
Med. Chem. Commun., 2013,4, 1513-1522

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    Development and evaluation of selective, reversible LSD1 inhibitors derived from fragments

    J. R. Hitchin, J. Blagg, R. Burke, S. Burns, M. J. Cockerill, E. E. Fairweather, C. Hutton, A. M. Jordan, C. McAndrew, A. Mirza, D. Mould, G. J. Thomson, I. Waddell and D. J. Ogilvie, Med. Chem. Commun., 2013, 4, 1513
    DOI: 10.1039/C3MD00226H

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