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. 2012 Sep 13;55(17):7378-91.
doi: 10.1021/jm3002845. Epub 2012 Sep 4.

Low molecular weight amidoximes that act as potent inhibitors of lysine-specific demethylase 1

Stuart Hazeldine  1 , Boobalan Pachaiyappan, Nora Steinbergs, Shannon Nowotarski, Allison S Hanson, Robert A Casero Jr, Patrick M Woster
Affiliations

Low molecular weight amidoximes that act as potent inhibitors of lysine-specific demethylase 1

Stuart Hazeldine et al. J Med Chem. .

Abstract

The recently discovered enzyme lysine-specific demethylase 1 (LSD1) plays an important role in the epigenetic control of gene expression, and aberrant gene silencing secondary to LSD1 dysregulation is thought to contribute to the development of cancer. We reported that (bis)guanidines, (bis)biguanides, and their urea- and thiourea isosteres are potent inhibitors of LSD1 and induce the re-expression of aberrantly silenced tumor suppressor genes in tumor cells in vitro. We now report a series of small molecule amidoximes that are moderate inhibitors of recombinant LSD1 but that produce dramatic changes in methylation at the histone 3 lysine 4 (H3K4) chromatin mark, a specific target of LSD1, in Calu-6 lung carcinoma cells. In addition, these analogues increase cellular levels of secreted frizzle-related protein (SFRP) 2, H-cadherin (HCAD), and the transcription factor GATA4. These compounds represent leads for an important new series of drug-like epigenetic modulators with the potential for use as antitumor agents.

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Figures

Figure 1
Figure 1
Structures of previously discovered LSD1 inhibitors 1c and 2d, the monoamine oxidase inhibitors tranylcypromine 3 and pargyline 4, and virtual screening hits 5–7.
Figure 2
Figure 2
Fold increase in the expression of SFRP2 in Calu-6 anaplastic epithelial lung carcinoma cells. Cells were treated with either 1 mM aminoguanidine (AG), 5 μM PN11144, 5 μM 2d or 10 μM of the indicated test compound for 24 or 48 hours. Each data point is the average of three determinations that in no case differed by more than 5%.
Figure 3
Figure 3
Fold increase in the expression of HCAD Calu-6 anaplastic epithelial lung carcinoma cells. Cells were treated with either 1 mM aminoguanidine (AG), 5 μM PN11144, 5 μM 2d or 10 μM of the indicated test compound for 24 or 48 hours. Each data point is the average of three determinations that in no case differed by more than 5%.
Figure 4
Figure 4
Fold increase in the expression of GATA4 in Calu-6 anaplastic epithelial lung carcinoma cells. Cells were treated with either 1 mM aminoguanidine (AG), 5 μM PN11144, 5 μM 2d or 10 μM of the indicated test compound for 24 or 48 hours. Each data point is the average of three determinations that in no case differed by more than 5%.
Figure 5
Figure 5
Graphic representation of binding mode of amidoxime 22 in the LSD1-CoREST complex active site. Panel A: Distance between the amidoxime functionality of 22 and N-5 of the flavin ring of FAD. Panel 3: Distance between the MET residue of the Forneris inhibitor and N-5 of the flavin ring of FAD. Panel B: Hydrogen bonding distances between 22 and amino acid residues THR 335, ALA 539 and TYR 761.
Figure 6
Figure 6
Results of in silico docking of amidoxime 22 in the active site of the LSD1-CoREST complex. The FAD cofactor is shown in red, and distances are in angstroms.
Scheme 1
Scheme 1
Scheme 2
Scheme 2
Scheme 3
Scheme 3
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