Plant Growth Regulator Daminozide Is a Selective Inhibitor of Human KDM2/7 Histone Demethylases

Rose, Nathan R.; Woon, Esther C. Y.; Tumber, Anthony; Walport, Louise J.; Chowdhury, Rasheduzzaman; Li, X S; King, Oliver N.; Lejeune, Clarisse; Ng, Stanley S.; Krojer, T.; Chan, Mun Chiang; Rydzik, Anna M.; Hopkinson, Richard J.; H, K; Daniel, M; Strain-Damerell, Claire; Gileadi, C.; Kochan, Grazyna; Leung, Ivanhoe K. H.; Dunford, J E; Yeoh, Kar Kheng; Ratcliffe, Peter J.; Burgess-Brown, N.; Delft, Frank von; Müller, Susanne; Marsden, Brian D.; Brennan, P.E.; McDonough, Michael A.; Oppermann, U.; Klose, Robert J.; Schofield, Christopher J.; Kawamura, Akane

doi:10.1021/jm300677j

Cited by 136 publications

(151 citation statements)

References 27 publications

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“…Most known KDM inhibitors are competitive with respect to 2OG, and as such, their inhibitor profiles can be similar; however, it is becoming increasingly evident that it is possible to identify inhibitors that discriminate between different subfamilies (26). Recently a small molecule inhibitor of KDM6A/B, GSK-J1, has been described (25).…”

Section: Resultsmentioning

confidence: 99%

Human UTY(KDM6C) Is a Male-specific Nϵ-Methyl Lysyl Demethylase

Walport

Hopkinson

Vollmar

et al. 2014

Journal of Biological Chemistry

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Background: UTY(KDM6C) has been reported previously to be inactive as a histone demethylase.Results: Crystallography reveals that the fold of the UTY(KDM6C) catalytic domain is highly conserved with those of KDM6A/B. UTY(KDM6C) catalyzes demethylation of Nϵ-methylated lysine histone peptides at Lys27.Conclusion: UTY(KDM6C) is a lysine demethylase that shows high structural similarity with KDM6A/B.Significance: UTY(KDM6C) is a functional Nϵ-methyl lysine demethylase.

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Section: Resultsmentioning

confidence: 99%

Human UTY(KDM6C) Is a Male-specific Nϵ-Methyl Lysyl Demethylase

Walport

Hopkinson

Vollmar

et al. 2014

Journal of Biological Chemistry

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187

183

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“…The JmjC KDM inhibitors, a separate class of inhibitors from those that target FAD-dependent KDMs, inhibit the removal of methyl-groups from histone lysines by exploiting the iron and α-KG dependent mechanism of JmjC KDMs (Figure 3). For example, daminozide 35 ( Figure 9B) is a selective α-KG competitive inhibitor of KDM2/7 that also chelates the central catalytic iron ion between its hydrazide carbonyl oxygen and dimethylamino nitrogen [159]. Modeling the active site of KDM2/7, the daminozide structure was optimized with an α-KG mimic and a longer alkyl chain 36 to serve as a lead structure in the development of more potent and selective KDM2/7 inhibitors [160].…”

Section: Lysine Demethylase Inhibitorsmentioning

confidence: 99%

Inhibitors of Enzymes Catalyzing Modifications to Histone Lysine Residues: Structure, Function and Activity

et al. 2016

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Gene expression is partly controlled by epigenetic mechanisms including histone-modifying enzymes. Some diseases are caused by changes in gene expression that can be mitigated by inhibiting histone-modifying enzymes. This review covers the enzyme inhibitors targeting histone lysine modifications. We summarize the enzymatic mechanisms of histone lysine acetylation, deacetylation, methylation and demethylation and discuss the biochemical roles of these modifications in gene expression and in disease. We discuss inhibitors of lysine acetylation, deacetylation, methylation and demethylation defining their structure-activity relationships and their potential mechanisms. We show that there are potentially indiscriminant off-target effects on gene expression even with the use of selective epigenetic enzyme inhibitors.

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“…The plant growth regulator daminozide is a KDM inhibitor selective for the KDM2/7 subfamily (IC50 values are 0.55, 1.5 and 2.1 mM for PHF8, KDM2A and KDM7A respectively and exhibits !60-fold selectivity for KDM2/ 7 demethylases over other histone demethylases and 2-oxoglurate oxygenases (IC50 > 100 mM)[19]. Treatment with 2 mM daminozide incremented H3K9 methylation in melanoma cells to similar levels as siRNA mediated KDM7 knockdown[20], reflecting good cell penetration.…”

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confidence: 90%