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Nonpeptidic propargylamines as inhibitors of lysine specific demethylase 1 (LSD1) with cellular activity.


ABSTRACT: 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.

SUBMITTER: Schmitt ML 

PROVIDER: S-EPMC4361900 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Nonpeptidic propargylamines as inhibitors of lysine specific demethylase 1 (LSD1) with cellular activity.

Schmitt Martin L ML   Hauser Alexander-Thomas AT   Carlino Luca L   Pippel Martin M   Schulz-Fincke Johannes J   Metzger Eric E   Willmann Dominica D   Yiu Teresa T   Barton Michelle M   Schüle Roland R   Sippl Wolfgang W   Jung Manfred M  

Journal of medicinal chemistry 20130905 18


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 contai  ...[more]

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