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

Martin L. Schmitt, Alexander Thomas Hauser, Luca Carlino, Martin Pippel, Johannes Schulz-Fincke, Eric Metzger, Dominica Willmann, Teresa Yiu, Michelle Barton, Roland Schüle, Wolfgang Sippl, Manfred Jung

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)7334-7342
Number of pages9
JournalJournal of Medicinal Chemistry
Issue number18
StatePublished - Sep 26 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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