Facile synthesis of substituted trans-2-arylcyclopropylamine inhibitors of the human histone demethylase LSD1 and monoamine oxidases A and B

Gooden, David M.; Schmidt, Dawn M. Z.; Pollock, Julie A.; Kabadi, Ami M.; McCafferty, Dewey G.

doi:10.1016/j.bmcl.2008.01.003

Cited by 69 publications

(60 citation statements)

References 19 publications

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“…11 A number of inhibitors based on the tranylcypromine scaffold have now been discovered, and in a few cases they have nanomolar IC 50 values against recombinant LSD1. 9, 12–17 In 2007, we described a series of (bis)guanidines and (bis)biguanides that act as potent LSD1 inhibitors, increase H3K4 methylation and promote the re-expression of aberrantly silenced tumor suppressor genes in vitro. 8 The lead compound emerging from these studies, verlindamycin (2, Figure 1, aka 2d), is synergistic with the deoxynucleotide-N-methyltransferase (DNMT) inhibitor 5-azacytidine (5-AC) in limiting tumor growth in an HCT116 xenograft study in athymic mice, 18 and has been shown to promote the re-expression of the silenced e-cadherin gene in acute myeloid leukemia cells in vitro.…”

Section: Introductionmentioning

confidence: 99%

Structure–activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures

Nowotarski

Pachaiyappan

Holshouser

et al. 2015

Bioorganic & Medicinal Chemistry

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Methylation at specific histone lysine residues is a critical post-translational modification that alters chromatin architecture, and dysregulated lysine methylation/demethylation is associated with the silencing of tumor suppressor genes. The enzyme lysine-specific demethylase 1 (LSD1) complexed to specific transcription factors catalyzes the oxidative demethylation of mono- and dimethyllysine 4 of histone H3 (H3K4me and H3K4me2 respectively). We have previously reported potent (bis)urea and (bis)thiourea LSD1 inhibitors that increase cellular levels of H3K4me and H3K4me2, promote the re-expression of silenced tumor suppressor genes and suppress tumor growth in vitro. Here we report the design additional (bis)urea and (bis)thiourea LSD1 inhibitors that feature 3-5-3 or 3-6-3 carbon backbone architectures. Three of these compounds displayed single-digit IC50 values in a recombinant LSD1 assay. In addition, compound 6d exhibited an IC50 of 4.2 μM against the Calu-6 human lung adenocarcinoma line, and 4.8 μM against the MCF7 breast tumor cell line, in an MTS cell viability assay. Following treatment with 6b–6d, Calu-6 cells exhibited a significant increase in the mRNA expression for the silenced tumor suppressor genes SFRP2, HCAD and p16, and modest increases in GATA4 message. The compounds described in this paper represent the most potent epigenetic modulators in this series, and have potential for use as antitumor agents.

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Section: Introductionmentioning

confidence: 99%

Structure–activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures

Nowotarski

Pachaiyappan

Holshouser

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Studies on LSD1 have identified several inhibitors, such as tranylcypromine, S2101, and CBB1007, which efficiently blocks LSD1-mediated demethylation of H3K4me2 [14][15][16]. H3K4me2 is an important histone mark that is frequently associated with gene activation, and recent studies using ChIP-seq data have shown that H3K4me2 has specific binding patterns on tissue-specific genes in human CD4+ T cells, neural tissues, and mouse brain tissues [17][18][19].…”

Section: Introductionmentioning

confidence: 98%

Inhibition of H3K4me2 Demethylation Protects Auditory Hair Cells from Neomycin-Induced Apoptosis

Cai

et al. 2014

Mol Neurobiol

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Aminoglycoside-induced hair cell loss is a major cause of hearing impairment in children and deserves more attention in medical research. Epigenetic mechanisms have been shown to protect hair cells from ototoxic drugs. In this study, we focused on the role of dimethylated histone H3K4 (H3K4me2) in hair cell survival. To investigate the effects of lysine-specific demethylase 1 (LSD1)--the histone demethylase primarily responsible for demethylating H3K4me2--on neomycin-induced hair cell loss, isolated cochleae were pretreated with LSD1 inhibitors followed by neomycin exposure. There was a severe loss of hair cells in the organ of Corti after neomycin exposure, and inhibition of LSD1 significantly protected against neomycin-induced hair cell loss. H3K4me2 expression in the nuclei of hair cells decreased after exposure to neomycin, and blocking the decreased expression of H3K4me2 with LSD1 inhibitors prevented hair cell loss. Local delivery of these inhibitors in vivo also protected hair cells from neomycin-induced ototoxicity and maintained the hearing threshold in mice as determined by auditory brain stem response. This inhibition of neomycin-induced apoptosis occurs via reduced caspase-3 activation. Together, our findings demonstrate the protective role for H3K4me2 against neomycin-induced hair cell loss and hearing loss.

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“…Some trans-2-PCPA analogues carrying 4-bromo, 4-methoxy, and 4-trifluoromethoxy substitutions at the benzene ring led to compounds (19)(20)(21) with similar or slightly improved activity against LSD1. 59 Interestingly, the introduction of a bulky, branched substituent at the 4 position of the benzene ring, able to occupy the wide space present in the LSD1 cavity surrounding the FAD cofactor and the AO domain, furnished tranylcypromine-based compounds such as 22-27 endowed with high potency against LSD1 and scarce or no activity against MAOs. 55,56 Compounds 22 and 23 were also reported to be active against a panel of cancer cell lines with growth inhibition 50% (GI 50 ) values ranging from 6.0 to 67 µM (Table 2), 55 whereas 26 was able to inhibit cell growth and induce differentiation in murine acute promyelocytic leukemia (APL) blasts as M Monographs a single agent and in APL-derived NB4 cells in synergy with retinoic acid (RA).…”

Section: Anti-mao-based Small Moleculesmentioning

confidence: 99%

Targeting Histone Demethylases: A New Avenue for the Fight against Cancer

2011

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In addition to genetic disorders, epigenetic alterations have been shown to be involved in cancer, through misregulation of histone modifications. Miswriting, misreading, and mis-erasing of histone acetylation as well as methylation marks can be actually associated with oncogenesis and tumor proliferation. Historically, methylation of Arg and Lys residues has been considered a stable, irreversible process due to the slow turnover of methyl groups in chromatin. The discovery in recent years of a large number of histone Lys demethylases (KDMs, belonging to either the amino oxidase or the JmjC family) totally changed this point of view and suggested a new role for dynamic histone methylation in biological processes. Since overexpression, alteration, or mutation of a number of KDMs has been found in many types of cancers, such enzymes could represent diagnostic tools as well as epigenetic targets to modulate for obtaining novel therapeutic weapons against cancer. The first little steps in this direction are described here.

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Facile synthesis of substituted trans-2-arylcyclopropylamine inhibitors of the human histone demethylase LSD1 and monoamine oxidases A and B

Abstract: A facile synthetic route to substituted trans-2-arylcyclopropylamines was developed to provide access to mechanism-based inhibitors of the human flavoenzyme oxidase lysine-specific histone demethylase LSD1 and related enzyme family members such as monoamine oxidases A and B.

Cited by 69 publications

References 19 publications

Structure–activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures

Structure–activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures

Inhibition of H3K4me2 Demethylation Protects Auditory Hair Cells from Neomycin-Induced Apoptosis

Targeting Histone Demethylases: A New Avenue for the Fight against Cancer

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