Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 18, Pages 7334-7342Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm400792m
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Funding
- Deutsche Forschungsgemeinschaft [Ju295/7-1, Si868/4-1, Schu688/11-1]
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Lysine demethylases play an important role in epigenetic regulation and thus in the development of diseases like cancer or neurodegenerative disorders. As the lysine specific demethylase 1 (LSD1/KDM1) has been strongly connected to androgen and estrogen dependent gene expression, it serves as a promising target for the therapy of hormone dependent cancer. Here, we report on the discovery of new small molecule inhibitors of LSD1 containing a propargylamine warhead, starting out from lysine containing substrate analogues. On the basis of these substrate mimicking inhibitors, we were able to increase potency by a combination of similarity-based virtual screening and subsequent synthetic optimization resulting in more druglike LSD1 inhibitors that led to histone hypermethylation in breast cancer cells.
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