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

James Hitchin, Julian Blagg, Rosemary Burke, Samantha Burns, Mark Cockerill, Emma Fairweather, Colin Hutton, Allan Jordan, Craig McAndrew, Amin Mirza, Daniel Mould, Graeme J. Thomson, Ian Waddell, Donald Ogilvie

Research output: Contribution to journalArticlepeer-review


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. © 2013 The Royal Society of Chemistry.
Original languageEnglish
Pages (from-to)1513-1522
Number of pages9
Issue number11
Publication statusPublished - Nov 2013


  • LSD1, reversible inhibitor, fragment based drug discovery, epigenetics

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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