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. Based on 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 lead to histone hypermethylation in breast cancer cells.

A Systematic Review of Histone Lysine‐Specific Demethylase 1 and Its Inhibitors

“…Besides, there are several articles that indicated the LSD1 inhibitory effect of pargyline by biochemical assay or cellular experiments with similar result obtained by LSD1 knockdown or 2‐PCPA . Moreover, some articles from different groups have proved the function of propargyl group, the potential necessary group for pargyline activity, which can form a covalent bond with LSD1 cofactor FAD . Recently, we also reported a new series of pyrimidine‐thiourea‐hybrids compounds with pargyline group, which are designed for LSD1 inhibitors.…”

Design of small molecule epigenetic modulators

“…124 These warhead-containing compounds were only modestly potent IC 50 = 22.2 μM for 42 ), and produced increases in H3K4me2 in MCF7 cells (1.6–1.7-fold) only at concentrations of ≥100 μM. Interestingly, although these compounds contain a propargyl moiety that is present in previously described inactivators of LSD1, no enzyme kinetic data was presented.…”

Discovery of Histone Demethylase Inhibitors

“…However, a variety of other scaffolds have already been presented as inhibitors of LSD1. The gamma-pyrone namoline (25) has been identified as a reversible inhibitor of LSD1 with a high selectivity over monoamine oxidases [90] and also propargylamines with a lysine or an aryloxypropanol scaffold have been found to inhibit LSD1 in the micromolar range [91]. Among these are (bis)ureas and (bis)biguanides [82], the first small molecule lysine demethylase inhibitors that were described, and their isosteres [83À85] as well as amidoxines [86], phenyloxazoles [87] and dithiocarbamates [88,89].…”