期刊
MEDCHEMCOMM
卷 4, 期 11, 页码 1513-1522出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c3md00226h
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资金
- Cancer Research UK [C480/A1141, C309/A8274]
- Cancer Research UK [11566] Funding Source: researchfish
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 mu M 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.
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