脱甲基酶
化学
赖氨酸
表观遗传学
生物化学
小分子
组蛋白
药物发现
癌症研究
基因
氨基酸
生物
作者
Martin Schmitt,Alexander Thomas Hauser,Luca Carlino,Martin Pippel,Johannes Schulz-Fincke,Eric Metzger,Dominica Willmann,Teresa T. Yiu,Michelle C. Barton,Roland Schüle,Wolfgang Sippl,Manfred Jung
摘要
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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