A structure-guided approach identified a selective inhibitor of H3K27me3 demethylases.

  • Major finding: A structure-guided approach identified a selective inhibitor of H3K27me3 demethylases.

  • Clinical relevance: Inhibition of H3K27me3 demethylation suppresses TNF-α production in primary macrophages.

  • Impact: These structural insights provide a framework for future development of histone demethylase inhibitors.

Modulation of histone lysine methylation is crucial for regulation of chromatin structure and gene expression and is frequently deregulated in cancer. The lysine-specific demethylase 6 (KDM6) subfamily includes ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX, also known as KDM6A) and jumonji domain containing 3 (JMJD3, also known as KDM6B), which specifically remove the repressive histone H3 lysine 27 trimethyl (H3K27me3) mark. The identification of selective small-molecule inhibitors of histone demethylases would provide insight into the activity and cellular functions of these enzymes and also establish potential avenues for reversing pathologic epigenetic states. Kruidenier and colleagues solved the crystal structure of the JMJD3 catalytic domain in complex with an H3K27me3 peptide and used the insights into interactions required for substrate specificity and recognition to guide the optimization of weak inhibitors discovered in a screen of 2 million compounds. The lead compound, GSK-J1, competed with enzymatic cofactors and interacted with the catalytic metal ion at 2 sites to induce a shift in its position, suggesting potential approaches for the further development of selective demethylase inhibitors. GSK-J1 selectively bound and inhibited JMJD3 and UTX in vitro and in cell extracts, and masking of the polar acid groups in the derivate compound GSK-J4 allowed cell penetration and inhibition of JMJD3-induced H3K27me3 loss. In human macrophages, where JMJD3 participates in the transcriptional response to inflammatory stimuli, GSK-J4 significantly reduced the production of the proinflammatory cytokine TNF-α in association with sustained H3K27me3 occupancy and prevention of RNA polymerase II binding at the TNFA promoter. The identification and characterization of a selective H3K27me3 inhibitor thus provides insight into the structural determinants and cellular roles of demethylase activity, which may benefit cancer epigenetic drug discovery efforts.

Kruidenier L, Chung C, Cheng Z, Liddle J, Che K, Joberty G, et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 2012;488:404–8.

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