Histone demethylases (HDMs) are epigenetic enzymes that remove a methyl group from histone tails, acting as erasers of the epigenetic code.1 Basing on their enzymatic mechanism, HDMs can be grouped into two classes: FAD-dependent HDMs (including monoaminoxidases) and Jumonji C domain containing HDMs that are Fe2+ and α-ketoglutarate-dependent hydrolases.2 The substrate residues of this latter include H3K4, H3K9, H3K27 and H3K36 at all methylation states. In particular, the focus of this study is JMJD3, that specifically demethylates 'Lys- 27' of histone H3.3 It has been reported that these lysine demethylases (JHDM) are associated with several diseases, such as bladder cancer, prostate carcinoma, breast cancer, Hodgkin lymphoma.4 With the aim of discovering new potential inhibitors of this HDM as attractive candidates for the development of anticancer drugs,4 we have designed and synthesized a small collection of 4-substituted-pyridine-2,6-dicarboxylic acids. These molecules contain as scaffold the dipicolinic acid, which has been selected from a large library of fragments through computational studies, suggesting a good interaction with the catalytic site of JMJD3. The experimental binding affinities of the synthesized molecules towards the target protein are currently under evaluation by Differential Scanning Fluorimetry assay (DSF) and further biological assays. References:

40 th "A. Corbella" International Summer School on Organic Synthesis - ISOS 2015

FOGLIA, ANTONIO;TERRACCIANO, Stefania;RICCIO, Raffaele;BIFULCO, Giuseppe;BRUNO, Ines
2015

Abstract

Histone demethylases (HDMs) are epigenetic enzymes that remove a methyl group from histone tails, acting as erasers of the epigenetic code.1 Basing on their enzymatic mechanism, HDMs can be grouped into two classes: FAD-dependent HDMs (including monoaminoxidases) and Jumonji C domain containing HDMs that are Fe2+ and α-ketoglutarate-dependent hydrolases.2 The substrate residues of this latter include H3K4, H3K9, H3K27 and H3K36 at all methylation states. In particular, the focus of this study is JMJD3, that specifically demethylates 'Lys- 27' of histone H3.3 It has been reported that these lysine demethylases (JHDM) are associated with several diseases, such as bladder cancer, prostate carcinoma, breast cancer, Hodgkin lymphoma.4 With the aim of discovering new potential inhibitors of this HDM as attractive candidates for the development of anticancer drugs,4 we have designed and synthesized a small collection of 4-substituted-pyridine-2,6-dicarboxylic acids. These molecules contain as scaffold the dipicolinic acid, which has been selected from a large library of fragments through computational studies, suggesting a good interaction with the catalytic site of JMJD3. The experimental binding affinities of the synthesized molecules towards the target protein are currently under evaluation by Differential Scanning Fluorimetry assay (DSF) and further biological assays. References:
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11386/4646598
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