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Structure based design of a new scaffold for cell-penetrating peptidic inhibitors of the histone demethylase PHF8.

Structure based design of a new scaffold for cell-penetrating peptidic inhibitors of the histone demethylase PHF8.
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Dorosz J, Olsen L, Seger ST, Steinhauer C, Bouras G, Helgstrand C, Wiuf A, Gajhede M,


Dorosz J, Olsen L, Seger ST, Steinhauer C, Bouras G, Helgstrand C, Wiuf A, Gajhede M, (click to view)

Dorosz J, Olsen L, Seger ST, Steinhauer C, Bouras G, Helgstrand C, Wiuf A, Gajhede M,

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Chembiochem : a European journal of chemical biology 2017 04 21() doi 10.1002/cbic.201700109

Abstract

The histone demethylase PHF8 catalyzes demethylation of mono- and di-methylated lysine 9 on histone H3 (H3K9me1/2) and is a transcriptional activator involved in development and cancer. Affinity and specificity of PHF8 towards H3K9me2 substrate is affected by interaction with both the catalytic domain and a PHD reader domain. The latter specifically recognizes tri-methylated lysine 4 on histone H3. A fragment of the histone H3 tail with tri-methylated lysine 4 was used as template for structure based design of a cyclic, cell-penetrating peptide that exhibits micromolar binding affinity to PHF8 in biochemical assays. The inhibitor has significantly lower affinity towards enzymes from the phylogenetically closest KDM2 subfamily, and also towards KDM3 and KDM6 subfamilies. Selectivity is only marginal towards an enzyme from the KDM4 family that share histone tail specificity with PHF8. It is a substrate of KDM5B implicating that the free N-terminus is not part of KDM5 enzyme substrate recognition machinery. The cyclic peptides ability to penetrate cells is achieved by incorporation of a sequence derived from the Trans-activator of transcription protein of HIV. The derived cyclic peptide can be used as a starting compound in the search for new more potent and selective PHF8 inhibitors.

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