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Issue 1, 2011
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Inhibition of the histone demethylase JMJD2E by 3-substituted pyridine 2,4-dicarboxylates

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Abstract

Based on structural analysis of the human 2-oxoglutarate (2OG) dependent JMJD2 histoneNε-methyl lysyl demethylase family, 3-substituted pyridine 2,4-dicarboxylic acids were identified as potential inhibitors with possible selectivity over other human 2OG oxygenases. Microwave-assisted palladium-catalysed cross coupling methodology was developed to install a diverse set of substituents on the sterically demanding C-3 position of a pyridine 2,4-dicarboxylate scaffold. The subsequently prepared di-acids were tested for in vitro inhibition of the histone demethylase JMJD2E and another human 2OG oxygenase, prolyl-hydroxylase domain isoform 2 (PHD2, EGLN1). A subset of substitution patterns yielded inhibitors with selectivity for JMJD2E over PHD2, demonstrating that structure-based inhibitor design can enable selective inhibition of histone demethylases over related human 2OG oxygenases.

Graphical abstract: Inhibition of the histone demethylase JMJD2E by 3-substituted pyridine 2,4-dicarboxylates

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Publication details

The article was received on 17 Aug 2010, accepted on 07 Oct 2010 and first published on 15 Nov 2010


Article type: Paper
DOI: 10.1039/C0OB00592D
Citation: Org. Biomol. Chem., 2011,9, 127-135
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    Inhibition of the histone demethylase JMJD2E by 3-substituted pyridine 2,4-dicarboxylates

    A. Thalhammer, J. Mecinović, C. Loenarz, A. Tumber, N. R. Rose, T. D. Heightman and C. J. Schofield, Org. Biomol. Chem., 2011, 9, 127
    DOI: 10.1039/C0OB00592D

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