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

43 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7334-7342
Number of pages9
JournalJournal of Medicinal Chemistry
Volume56
Issue number18
DOIs
StatePublished - Sep 26 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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