General Description
A bisguanidine polyamine analogue that exhibits noncompetitive and specific LSD1 inhibition, with 14.1% remaining LSD1 activity at 10 μM
in vitro, and is shown to significantly increase methylation at the histone 3 lysine 4 chromatin mark (H3K4me1 and H3K4me2) dose-dependently from 0.25 μM to 10 μM, without affecting global H3K9me2 (which is not a LSD1 substrate) levels in HCT116 human colon carcinoma cells. This compound induces reexpression of several epigenetically silenced genes including
SFRP1,
SFRP4,
SFRP5, and
GATA5 more effectively when compared with siRNA treatment, particularly in the case of
SFRP4 and
SFRP5.
Biological Activity
lysine-specific demethylase inhibitor (1c) is a lysine-specific demethylase inhibitor.lysine-specific demethylase 1 (lsd1) is the first of several protein lysine demethylases identified. through a fad-dependent oxidative reaction, lsd1 could specifically remove histone h3k4me2 to h3k4me1 or h3k4me0. when forming a complex with androgen receptor, lsd1 alters its substrates to h3k9me2. the lsd1 complex regulates a coordinated histone modification switch via enzymatic activities and histone modification readers.
in vitro
lysine-specific demethylase inhibitor (1c) was identified as a bisguanidine polyamine analogue exhibiting noncompetitive and specific lsd1 inhibition, with 14.1% in vitro lsd1 activity at 10 μm. lysine-specific demethylase inhibitor (1c) at 0.25 μm to 10 μm could significantly and dose-dependently increase methylation at the histone 3 lysine 4 chromatin mark, h3k4me1 and h3k4me2, without affecting global h3k9me2 levels in hct116 human colon carcinoma cells. lysine-specific demethylase inhibitor (1c) could also induce expression of several epigenetically silenced genes, such as sfrp1, sfrp4, sfrp5, and gata5, particularly in the case of sfrp4 and sfrp5 [1].
References
[1] sharma sk, wu y, steinbergs n, crowley ml, hanson as, casero ra, woster pm. (bis)urea and (bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators.j med chem. 2010 jul 22;53(14):5197-212.
