Low Molecular Weight Amidoximes that Act as Potent Inhibitors of Lysine-Specific Demethylase 1

Hazeldine, Stuart; Pachaiyappan, Boobalan; Steinbergs, Nora; Nowotarski, Shannon L.; Hanson, Allison S.; Casero, Robert A.; Woster, Patrick M.

doi:10.1021/jm3002845

Cited by 68 publications

(41 citation statements)

References 52 publications

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“…25 The crystal structure of LSD1/CoREST (PDB 2V1D) was prepared using PrepWizard, and SiteMap was then used to assess efficient binding within the LSD1 histone-binding pocket. Lowest energy conformers of 3D compounds were determined and docked in the LSD1 active site using Glide.…”

Section: Resultsmentioning

confidence: 99%

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3,5-Diamino-1,2,4-triazoles as a novel scaffold for potent, reversible LSD1 (KDM1A) inhibitors

et al. 2014

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The chromatin remodeling amine oxidase lysine-specific demethylase 1 (LSD1) has become an attractive target for the design of specific inhibitors with therapeutic potential. We, and others, have described LSD1 inhibitors that have potential as antitumor agents. Many of the currently known LSD1 inhibitors are poor drug candidates, or are structurally based on the tranylcypromine backbone, thus increasing the potential for off-target effects mediated by other amine oxidases. We now describe a series of potent LSD1 inhibitors based on a novel 1,2,4-triazole scaffold; these inhibitors show a high degree of specificity for LSD1 in vitro, and cause increases in cellular histone 3 dimethyllysine 4 (H3K4me2), a gene transcription activating mark. Importantly, these inhibitors are not toxic to mammalian cells in vitro, and thus they may show utility in the treatment of epigenetically-based diseases where cell death is not a desired endpoint Figure 1. Structures of LSD1 inhibitors 1, verlindamycin 2, (bis)thioureas 3, amidoxime 4, cyclic peptide 5, N3-(2-chloro-6-phenoxybenzyl)-4H-1,2,4-triazole-3,5-diamine 6 and N3,N5-bis(2-methoxybenzyl)-1H-1,2,4-triazole-3,5-diamine 7.

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Section: Resultsmentioning

confidence: 99%

“…The synthesis and biological evaluation of other lead compounds identified in this screen have been previously published. 25 In the present study, two hits from the virtual screen, compounds 6 and 7 (Figure 1), were identified, and these compounds, as well as related analogues 8–20 , were purchased and evaluated (Table 1). …”

Section: Resultsmentioning

confidence: 99%

3,5-Diamino-1,2,4-triazoles as a novel scaffold for potent, reversible LSD1 (KDM1A) inhibitors

et al. 2014

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“…Each compound was initially evaluated at a 10 μ M concentration, and an IC 50 value was determined for the most active peptide analogue 9 over a concentration range of 0.01–50 μ M. The known LSD1 inhibitor verlindamycin 3 6 was used as a positive control and produced 95% inhibition of the enzyme at 10 μ M. This level of inhibition is consistent with previously published values. 27,28 As shown in Table 1, all cyclic peptides inhibited the enzyme between 39 and 94%, following the relative rank order of 9 > 7 > 13 > 11 = 10 > 12 > 8 . Thus, the [Met] 4 H3 (1-21)-NH 2 cyclic peptide 9, in which the lactam bridge was between Lys5 and Glu10, produced the greatest LSD1 inhibitory activity, while cyclic [Lys2, Glu14] [Met] 4 H3 (1-21)-NH 2 8 displayed the least inhibitory activity.…”

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confidence: 95%

Synthesis and Evaluation of Novel Cyclic Peptide Inhibitors of Lysine-Specific Demethylase 1

Kumarasinghe

Woster

2013

ACS Med. Chem. Lett.

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Lysine specific demethylase 1 (LSD1) selectively removes methyl groups from mono- and dimethylated histone 3 lysine 4 (H3K4), resulting in gene silencing. LSD1 is overexpressed in many human cancers, resulting in aberrant silencing of tumor suppressor genes. Thus, LSD1 is a validated target for the discovery of antitumor agents. Using a ligand-based approach, we designed and synthesized a series of cyclic and linear peptides that are effective inhibitors of LSD1. Linear peptide 7 and cyclic peptide 9 inhibited LSD1 in vitro by 91 and 94%, respectively, at a concentration of 10 μM. Compound 9 was a potent LSD1 inhibitor (IC50 2.1 μM; Ki 385 nM) and had moderate antitumor activity in the MCF-7 and Calu-6 cell lines in vitro. Importantly, 9 is significantly more stable to hydrolysis in rat plasma than the linear analogue 7. The cyclic peptides described herein represent important lead structures in the search for inhibitors of flavin-dependent histone demethylases.

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“…Apart from the polyamine analogues and guanidium compounds, Namoline is a small-molecule compound reported to inhibit LSD1 selectively over MAOs, although its potency is not high (IC 50 = 51 μM) 109 . Several research groups have developed other noncovalent LSD1 inhibitors 110-118 . The IC 50 values of some of these compounds are only in the micromolar range, however, inhibitors with submicromolar inhibitory potency have recently started to appear (Table 3).…”

Section: Introductionmentioning

confidence: 99%

Structural insight into inhibitors of flavin adenine dinucleotide-dependent lysine demethylases

Niwa¹,

Umehara

2017

Epigenetics

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Until 2004, many researchers believed that protein methylation in eukaryotic cells was an irreversible reaction. However, the discovery of lysine-specific demethylase 1 in 2004 drastically changed this view and the concept of chromatin regulation. Since then, the enzymes responsible for lysine demethylation and their cellular substrates, biological significance, and selective regulation have become major research topics in epigenetics and chromatin biology. Many cell-permeable inhibitors for lysine demethylases have been developed, including both target-specific and nonspecific inhibitors. Structural understanding of how these inhibitors bind to lysine demethylases is crucial both for validation of the inhibitors as chemical probes and for the rational design of more potent, target-specific inhibitors. This review focuses on published small-molecule inhibitors targeted at the two flavin adenine dinucleotide-dependent lysine demethylases, lysine-specific demethylases 1 and 2, and how the inhibitors interact with the tertiary structures of the enzymes.

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Low Molecular Weight Amidoximes that Act as Potent Inhibitors of Lysine-Specific Demethylase 1

Cited by 68 publications

References 52 publications

3,5-Diamino-1,2,4-triazoles as a novel scaffold for potent, reversible LSD1 (KDM1A) inhibitors

3,5-Diamino-1,2,4-triazoles as a novel scaffold for potent, reversible LSD1 (KDM1A) inhibitors

Synthesis and Evaluation of Novel Cyclic Peptide Inhibitors of Lysine-Specific Demethylase 1

Structural insight into inhibitors of flavin adenine dinucleotide-dependent lysine demethylases

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