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A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1.

ABSTRACT: The 2-oxoglutarate (2OG)-dependent Jumonji?C domain (JmjC) family is the largest family of histone lysine demethylases. There is interest in developing small-molecule probes that modulate JmjC activity to investigate their biological roles. 5-Carboxy-8-hydroxyquinoline (IOX1) is the most potent broad-spectrum inhibitor of 2OG oxygenases, including the JmjC demethylases, reported to date; however, it suffers from low cell permeability. Here, we describe structure-activity relationship studies leading to the discovery of an n-octyl ester form of IOX1 with improved cellular potency (EC50 value of 100 to 4??M). These findings are supported by in vitro inhibition and selectivity studies, docking studies, activity versus toxicity analysis in cell cultures, and intracellular uptake measurements. The n-octyl ester was found to have improved cell permeability; it was found to inhibit some JmjC demethylases in its intact ester form and to be more selective than IOX1. The n-octyl ester of IOX1 should find utility as a starting point for the development of JmjC inhibitors and as a use as a cell-permeable tool compound for studies investigating the roles of 2OG oxygenases in epigenetic regulation.

SUBMITTER: Schiller R

PROVIDER: S-EPMC4503230 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1.

Schiller Rachel R Scozzafava Giuseppe G Tumber Anthony A Wickens James R JR Bush Jacob T JT Rai Ganesha G Lejeune Clarisse C Choi Hwanho H Yeh Tzu-Lan TL Chan Mun Chiang MC Mott Bryan T BT McCullagh James S O JS Maloney David J DJ Schofield Christopher J CJ Kawamura Akane A

ChemMedChem 20140206 3

The 2-oxoglutarate (2OG)-dependent Jumonji C domain (JmjC) family is the largest family of histone lysine demethylases. There is interest in developing small-molecule probes that modulate JmjC activity to investigate their biological roles. 5-Carboxy-8-hydroxyquinoline (IOX1) is the most potent broad-spectrum inhibitor of 2OG oxygenases, including the JmjC demethylases, reported to date; however, it suffers from low cell permeability. Here, we describe structure-activity relationship studies lea ...[more]

PMID: 24504543

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Project description:The N ε-methyl lysine status of histones is important in the regulation of eukaryotic transcription. The Fe(ii) and 2-oxoglutarate (2OG) -dependent JmjC domain enzymes are the largest family of histone N ε-methyl lysine demethylases (KDMs). The human KDM4 subfamily of JmjC KDMs is linked with multiple cancers and some of its members are medicinal chemistry targets. We describe the use of combined molecular dynamics (MD) and Quantum Mechanical/Molecular Mechanical (QM/MM) methods to study the mechanism of KDM4A, which catalyzes demethylation of both tri- and di-methylated forms of histone H3 at K9 and K36. The results show that the oxygen activation at the active site of KDM4A is optimized towards the generation of the reactive Fe(iv)-oxo intermediate. Factors including the substrate binding mode, correlated motions of the protein and histone substrates, and molecular orbital control synergistically contribute to the reactivity of the Fe(iv)-oxo intermediate. In silico substitutions were performed to investigate the roles of residues (Lys241, Tyr177, and Asn290) in substrate orientation. The Lys241Ala substitution abolishes activity due to altered substrate orientation consistent with reported experimental studies. Calculations with a macrocyclic peptide substrate analogue reveal that induced conformational changes/correlated motions in KDM4A are sequence-specific in a manner that influences substrate binding affinity. Second sphere residues, such as Ser288 and Thr289, may contribute to KDM4A catalysis by correlated motions with active site residues. Residues that stabilize key intermediates, and which are predicted to be involved in correlated motions with other residues in the second sphere and beyond, are shown to be different in KDM4A compared to those in another JmjC KDM (PHF8), which acts on H3K9 di- and mono-methylated forms, suggesting that allosteric type inhibition is of interest from the perspective of developing selective JmjC KDM inhibitors.

Project description:BackgroundHistone methylation occurs primarily on lysine residues and requires a set of enzymes capable of reading, writing, and erasing to control its establishment and deletion, which is essential for maintaining chromatin structure and gene expression. Histone methylation and demethylation are contributed to plant growth and development, and are involved in adapting to environmental stresses. The JmjC domain-containing proteins are extensively studied for their function in histone lysine demethylation in plants, and play a critical role in sustaining histone methylation homeostasis.ResultsIn this study, a total of 21 JmjC domain-containing histone demethylase proteins (JHDMs) in birch were identified and classified into five subfamilies based on structural characteristics and phylogenetic relationships among Arabidopsis, rice, maize, and birch. Although the BpJMJ genes displayed significant schematic variation, their distribution on the chromosomes is relatively uniform. Additionally, the BpJMJ genes in birch have never experienced a tandem-duplication event proved by WGD analysis and were remaining underwent purifying selection (Ka/Ks < < 1). A typical JmjC domain was found in all BpJMJ genes, some of which have other essential domains for their functions. In the promoter regions of BpJMJ genes, cis-acting elements associated with hormone and abiotic stress responses were overrepresented. Under abiotic stresses, the transcriptome profile reveals two contrasting expression patterns within 21 BpJMJ genes. Furthermore, it was established that most BpJMJ genes had higher expression in young tissues under normal conditions, with BpJMJ06/16 having the highest expression in germinating seeds and participating in the regulation of BpGA3ox1/2 gene expression. Eventually, BpJMJ genes were found to directly interact with genes involved in the "intracellular membrane" in respond to cold stress.ConclusionsThe present study will provide a foundation for future experiments on histone demethylases in birch and a theoretical basis for epigenetic research on growth and development in response to abiotic stresses.

Project description:Histone modification is an important epigenetic modification that controls gene transcriptional regulation in eukaryotes. Histone methylation is accomplished by histone methyltransferase and can occur on two amino acid residues, arginine and lysine. JumonjiC (JmjC) domain-containing histone demethylase regulates gene transcription and chromatin structure by changing the methylation state of the lysine residue site and plays an important role in plant growth and development. In this study, we carried out genome-wide identification and comprehensive analysis of JmjC genes in the allotetraploid cotton species Gossypium hirsutum. In total, 50 JmjC genes were identified and in G. hirsutum, and 25 JmjC genes were identified in its two diploid progenitors, G. arboreum and G. raimondii, respectively. Phylogenetic analysis divided these JmjC genes into five subfamilies. A collinearity analysis of the two subgenomes of G. hirsutum and the genomes of G. arboreum and G. raimondii uncovered a one-to-one relationship between homologous genes of the JmjC gene family. Most homologs in the JmjC gene family between A and D subgenomes of G. hirsutum have similar exon-intron structures, which indicated that JmjC family genes were conserved after the polyploidization. All G. hirsutumJmjC genes were found to have a typical JmjC domain, and some genes also possess other special domains important for their function. Analysis of promoter regions revealed that cis-acting elements, such as those related to hormone and abiotic stress response, were enriched in G. hirsutum JmjC genes. According to a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, most G. hirsutumJmjC genes had high abundance expression at developmental stages of fibers, suggesting that they might participate in cotton fiber development. In addition, some G. hirsutumJmjC genes were found to have different degrees of response to cold or osmotic stress, thus indicating their potential role in these types of abiotic stress response. Our results provide useful information for understanding the evolutionary history and biological function of JmjC genes in cotton.

Dataset Information

A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1.

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A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1.

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