Synthesis and evaluation of 3-amino/guanidine substituted phenyl oxazoles as a novel class of LSD1 inhibitors with anti-proliferative properties

Abstract

A series of functionalized phenyl oxazole derivatives was designed, synthesized and screened in vitro for their activities against LSD1 and for effects on viability of cervical and breast cancer cells, and in vivo for effects using zebrafish embryos. These compounds are likely to act via multiple epigenetic mechanisms specific to cancer cells including LSD1 inhibition.Histones are proteins that bind to DNA and facilitate efficient 'packing' of DNA in eukaryotic cells. 1 They are highly basic in nature due to the presence of positively charged amino acid side chains causing the DNA to fold around them into compact structures (nucleosomes). The ability of histones to regulate gene expression is controlled by post-translational modifications on the N-terminal (and likely C-terminal) "tails" of the core histones which project out of the nucleosome. Modifications including phosphorylation, acetylation, methylation, ubiquitination, sumoylation and biotinylation have been identified on the histone tails. 2 The cellular roles of histone lysine acetylation/deacetylation are the best characterized of the histone modifications -acetylation normally activates transcription whereas deacetylation deactivates this process. 3 Although there are clear links to disease, 4-8 the role of histone methylation is much less understood and appears to be context dependent.LSD1 (lysine specific demethylase 1) was the first histone demethylase identified. Its discovery significantly advanced the understanding of epigenetic regulation of gene expression, changing the paradigm that methylation is a non-reversible feature of histones. 9 Histone methylation/demethylation has since been found to be an important epigenetic modification linked to activation as well as repression of transcription. Two types of histone demethylases have been discovered. The flavin-dependent demethylase LSD1 acts on lysine 4 and lysine 9 of histone H3 (H3K4 and H3K9). LSD1 selectively catalyzes the oxidation of the methyl group of mono-and dimethylated lysines resulting in an imine intermediate and generation of hydrogen peroxide. The imine product is non-enzymatically hydrolysed to generate a carbinolamine resulting in demethylated lysine and formaldehyde release. 10 The other major class, i.e. Jumonji domain-containing histone demethylases, are Fe(II) and 2-oxoglutarate dependent oxygenases that act on mono-, di-and trimethylated Lys and methylated Arg residues depending on the particular enzymes. 11 Histone demethylase activity is associated with several pathological states. Increased LSD1 expression in prostate tumors correlates significantly with relapse during therapy. 6,7 Suppressed LSD1 expression is associated with vascular smooth muscle cell inflammatory damage in a mouse model of diabetes. 8 Demethylation of p53 (tumor suppressor) by LSD1 prevents p53 interaction with its co-activator 53BP1. 5 Activation of the telomerase reverse transcriptase (hTERT) gene is known to be dependent on LSD1 levels and recruitment to the hTERT promoter. 4 Studies on LSD1 hav...

KDM1 class flavin‐dependent protein lysine demethylases

“…Merging key pharmacophoric features of reported KDM1A inhibitors, Dulla and coworkers recently reported the development of 3‐amino/guanidine substituted phenyl oxazole‐containing inhibitors . Following treatment of cultured cells with nanomolar inhibitor concentrations, viability decreased as compared to the low micromolar range observed for inhibition of KDM1A in vitro .…”

Identification of Novel Selective Lysine‐Specific Demethylase 1 (LSD1) Inhibitors Using a Pharmacophore‐Based Virtual Screening Combined with Docking

“…A pharmacophore of LSD1 inhibitors was constructed. Firstly, 22 known compounds were selected as the training set in this study . Their structures and biological activities are shown in Figure S2.…”

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

“…To obtain more selective inhibitors of LSD1, Dulla et al. designed a series of phenyl oxazole derivatives by integrating the key pharmacophore of biguanide polyamine, polypeptide and 2‐PCPA . Among them, compound 27 (Fig.…”

“…To obtain more selective inhibitors of LSD1, Dulla et al designed a series of phenyl oxazole derivatives by integrating the key pharmacophore of biguanide polyamine, polypeptide and 2-PCPA. 177 Among them, compound 27 ( Fig. 9) was a high-efficiency LSD1 inhibitor and could significantly suppress the proliferation of the human breast cancer cell MDA-MB-231 and human cervical cancer cell HeLa.…”