Identification of catechols as histone–lysine demethylase inhibitors

Nielsen, Anders L.; Kristensen, Line H.; Stephansen, Karen Boutrup; Kristensen, Jan Bach; Helgstrand, Charlotte; Lees, Michael; Cloos, Paul A.; Helin, Kristian; Gajhede, Michael; Olsen, Lars

doi:10.1016/j.febslet.2012.03.001

Cited by 35 publications

(23 citation statements)

References 24 publications

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“…Consistent with this, lower IC 50 values for these catechols were observed in the presence of 15 M Fe(II) than in the presence of 50 M Fe(II). Furthermore, caffeic acid was identified as an inhibitor of JMJD2C/KDM4C and UTX/KDM6A (29).…”

Section: Resultsmentioning

confidence: 99%

Identification of Small Molecule Inhibitors of Jumonji AT-rich Interactive Domain 1B (JARID1B) Histone Demethylase by a Sensitive High Throughput Screen

Sayegh

Cao

Zou

et al. 2013

Journal of Biological Chemistry

122

108

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Background: JARID1B is an H3K4 histone demethylase and an attractive target for cancer therapy.Results: High throughput screen identified novel compounds that can inhibit JARID1B demethylase activity. Conclusion: Drug-like small molecules can be identified to inhibit JARID1B. Significance: The identified JARID1B inhibitors are lead compounds that can be developed into anti-cancer epigenetic drugs.

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Section: Resultsmentioning

confidence: 99%

Identification of Small Molecule Inhibitors of Jumonji AT-rich Interactive Domain 1B (JARID1B) Histone Demethylase by a Sensitive High Throughput Screen

Sayegh

Cao

Zou

et al. 2013

Journal of Biological Chemistry

122

108

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“…Several general inhibitors of JmjC demethylases have been identified including the α-ketoglutaric acid mimics N-oxalylglycine, 93 , 94 methylstat 95 and 2,4-dicarboxypyridine; the iron-chelating agent deferoxamine 95 ; the pyridine hydrazone JIB-04 96 and catechols 97 . Unfortunately, these inhibitors are selective against some or all JmjC enzymes but are unable to target one specific JmjC member.…”

Section: Targeting Utx By Small Molecule Inhibitorsmentioning

confidence: 99%

The H3K27me3 demethylase UTX in normal development and disease

2014

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In 2007, the Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) was identified as a histone demethylase that specifically targets di- and tri-methyl groups on lysine 27 of histone H3 (H3K27me2/3). Since then, UTX has been proven essential during normal development, as it is critically required for correct reprogramming, embryonic development and tissue-specific differentiation. UTX is a member of the MLL2 H3K4 methyltransferase complex and its catalytic activity has been linked to regulation of HOX and RB transcriptional networks. In addition, an H3K27me2/3 demethylase independent function for UTX was uncovered in promoting general chromatin remodeling in concert with the BRG1-containing SWI/SNF remodeling complex. Constitutional inactivation of UTX causes a specific hereditary disorder called the Kabuki syndrome, whereas somatic loss of UTX has been reported in a variety of human cancers. Here, we compile the breakthrough discoveries made from the first disclosure of UTX as a histone demethylase till the identification of disease-related UTX mutations and specific UTX inhibitors.

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“…Both JARID1A and JARID1B appear to contribute to retinoblastoma-mediated gene silencing during cellular senescence [26]. The search of in vivo inhibitors of JARID enzymatic activity is therefore very active, although only one of the HDM inhibitors which were found so far was shown to specifically inhibit H3K4 modification in vivo and in vitro [27], while all the others [28]–[31] seem to have more general and pleiotropic effects. In order to screen for specific H3K4 demethylase inhibitors, we developed an experimental system based on S.cerevisiae , taking advantage of the fact that this yeast contains only one H3K4-specific JHDM, i.e.…”

Section: Introductionmentioning

confidence: 99%

An High-Throughput In Vivo Screening System to Select H3K4-Specific Histone Demethylase Inhibitors

et al. 2014

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BackgroundHistone demethylases (HDMs) have a prominent role in epigenetic regulation and are emerging as potential therapeutic cancer targets. The search for small molecules able to inhibit HDMs in vivo is very active but at the present few compounds were found to be specific for defined classes of these enzymes.Methodology/Principal FindingsIn order to discover inhibitors specific for H3K4 histone demethylation we set up a screening system which tests the effects of candidate small molecule inhibitors on a S.cerevisiae strain which requires Jhd2 demethylase activity to efficiently grow in the presence of rapamycin. In order to validate the system we screened a library of 45 structurally different compounds designed as competitive inhibitors of α -ketoglutarate (α-KG) cofactor of the enzyme, and found that one of them inhibited Jhd2 activity in vitro and in vivo. The same compound effectively inhibits human Jumonji AT-Rich Interactive Domain (JARID) 1B and 1D in vitro and increases H3K4 tri-methylation in HeLa cell nuclear extracts (NEs). When added in vivo to HeLa cells, the compound leads to an increase of tri-methyl-H3K4 (H3K4me3) but does not affect H3K9 tri-methylation. We describe the cytostatic and toxic effects of the compound on HeLa cells at concentrations compatible with its inhibitory activity.Conclusions/SignificanceOur screening system is proved to be very useful in testing putative H3K4-specific HDM inhibitors for the capacity of acting in vivo without significantly altering the activity of other important 2-oxoglutarate oxygenases.

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Identification of catechols as histone–lysine demethylase inhibitors

Cited by 35 publications

References 24 publications

Identification of Small Molecule Inhibitors of Jumonji AT-rich Interactive Domain 1B (JARID1B) Histone Demethylase by a Sensitive High Throughput Screen

Identification of Small Molecule Inhibitors of Jumonji AT-rich Interactive Domain 1B (JARID1B) Histone Demethylase by a Sensitive High Throughput Screen

The H3K27me3 demethylase UTX in normal development and disease

An High-Throughput In Vivo Screening System to Select H3K4-Specific Histone Demethylase Inhibitors

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