Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives

Westaway, Susan M.; Preston, Alex; Barker, Michael D.; Brown, Fiona; Brown, Jack A.; Campbell, Matthew; Chung, Chun‐wa; Diallo, Hawa; Douault, Clement; Drewes, Gerard; Eagle, Robert A.; Gordon, Laurie J.; Haslam, Carl; Hayhow, Thomas G.; Humphreys, P. G.; Joberty, Gérard; Katso, Roy; Kruidenier, Laurens; Leveridge, Melanie; Liddle, John; Mosley, J.; Muelbaier, Marcel; Randle, Rebecca A.; Rioja, Inma; Rueger, Anne; Seal, Gail A.; Sheppard, Robert J.; Singh, Onkar; Taylor, Joanna; Thomas, Pamela J.; Thomson, Douglas W.; Wilson, David M.; Lee, Kevin; Prinjha, Rab K.

doi:10.1021/acs.jmedchem.5b01537

Cited by 53 publications

(45 citation statements)

References 23 publications

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“…SPE-MS requires only small amounts of substrates/enzymes for analysis and has been successfully applied to monitoring the activity of 2OG oxygenases by measuring mass shifts, i.e. +16 Da for hydroxylation and -14 Da for demethylation (41)(42)(43)(44)(45). We aimed to combine SPE-MS with the use of stable substrate analogues in which the non-canonical Cys 3-4 EGFD disulfide bond was replaced with a stable thioether.…”

Section: Development Of An Efficient Asph Activity Assaymentioning

confidence: 99%

Kinetic parameters of human aspartate/asparagine–β-hydroxylase suggest that it has a possible function in oxygen sensing

Brewitz

Tumber

Schofield

2020

Journal of Biological Chemistry

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Human aspartate/asparagine–β-hydroxylase (AspH) is a 2-oxoglutarate (2OG)–dependent oxygenase that catalyzes the post-translational hydroxylation of Asp and Asn residues in epidermal growth factor–like domains (EGFDs). Despite its biomedical significance, studies on AspH have long been limited by a lack of assays for its isolated form. Recent structural work has revealed that AspH accepts substrates with a noncanonical EGFD disulfide connectivity (i.e. the Cys 1–2, 3–4, 5–6 disulfide pattern). We developed stable cyclic thioether analogues of the noncanonical EGFD AspH substrates to avoid disulfide shuffling. We monitored their hydroxylation by solid-phase extraction coupled to MS. The extent of recombinant AspH-catalyzed cyclic peptide hydroxylation appears to reflect levels of EGFD hydroxylation observed in vivo, which vary considerably. We applied the assay to determine the kinetic parameters of human AspH with respect to 2OG, Fe(II), l-ascorbic acid, and substrate and found that these parameters are in the typical ranges for 2OG oxygenases. Of note, a relatively high Km for O2 suggested that O2 availability may regulate AspH activity in a biologically relevant manner. We anticipate that the assay will enable the development of selective small-molecule inhibitors for AspH and other human 2OG oxygenases.

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Section: Development Of An Efficient Asph Activity Assaymentioning

confidence: 99%

Kinetic parameters of human aspartate/asparagine–β-hydroxylase suggest that it has a possible function in oxygen sensing

Brewitz

Tumber

Schofield

2020

Journal of Biological Chemistry

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“…Although inhibitors have been reported for JmjC-containing KDMs (Bavetsias et al., 2016, Gehling et al., 2016, Horton et al., 2016, Itoh et al., 2015, McAllister et al., 2016, Vinogradova et al., 2016, Westaway et al., 2016a, Westaway et al., 2016b, Wu et al., 2016), most of the published compounds have limitations such as lack of selectivity or cytotoxicity. Bavetsias et al.…”

Section: Introductionmentioning

confidence: 99%

Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells

Tumber

Nuzzi

Hookway

et al. 2017

Cell Chemical Biology

107

102

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SummaryMethylation of lysine residues on histone tail is a dynamic epigenetic modification that plays a key role in chromatin structure and gene regulation. Members of the KDM5 (also known as JARID1) sub-family are 2-oxoglutarate (2-OG) and Fe2+-dependent oxygenases acting as histone 3 lysine 4 trimethyl (H3K4me3) demethylases, regulating proliferation, stem cell self-renewal, and differentiation. Here we present the characterization of KDOAM-25, an inhibitor of KDM5 enzymes. KDOAM-25 shows biochemical half maximal inhibitory concentration values of <100 nM for KDM5A-D in vitro, high selectivity toward other 2-OG oxygenases sub-families, and no off-target activity on a panel of 55 receptors and enzymes. In human cell assay systems, KDOAM-25 has a half maximal effective concentration of ∼50 μM and good selectivity toward other demethylases. KDM5B is overexpressed in multiple myeloma and negatively correlated with the overall survival. Multiple myeloma MM1S cells treated with KDOAM-25 show increased global H3K4 methylation at transcriptional start sites and impaired proliferation.

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“…Extensive efforts have been devoted to develop inhibitors against the Jumonji family of histone lysine demethylases (Bavetsias et al, 2016; Heinemann et al, 2014; Kruidenier et al, 2012; Rotili et al, 2014; Wang et al, 2013; Westaway et al, 2016a; Westaway et al, 2016b). Some of these inhibitors, such as KDM5-C49 and its cell permeable ethyl ester derivative, KDM5-C70 , are proposed to be potent and selective inhibitors of KDM5 demethylases in vitro and in cells (Patent WO2014053491).…”

Section: Introductionmentioning

confidence: 99%

Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds

Horton

Liu

Gale

et al. 2016

Cell Chemical Biology

105

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SUMMARY The KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases removes methyl groups from methylated lysine 4 of histone H3. Accumulating evidence supports a role for KDM5 family members as oncogenic drivers. We compare the in vitro inhibitory properties and binding affinity of ten diverse compounds with all four family members, and present the crystal structures of the KDM5A linked Jumonji domain in complex with eight of these inhibitors in the presence of Mn(II). All eight inhibitors structurally examined occupy the binding site of α-ketoglutarate, but differ in their specific binding interactions, including the number of ligands involved in metal coordination. We also observed inhibitor-induced conformational changes in KDM5A, particularly those residues involved in the binding of α-ketoglutarate, the anticipated peptide substrate, and intra-molecular interactions. We discuss how particular chemical moieties contribute to inhibitor potency and suggest strategies that might be utilized in the successful design of selective and potent epigenetic inhibitors.

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Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives

Cited by 53 publications

References 23 publications

Kinetic parameters of human aspartate/asparagine–β-hydroxylase suggest that it has a possible function in oxygen sensing

Kinetic parameters of human aspartate/asparagine–β-hydroxylase suggest that it has a possible function in oxygen sensing

Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells

Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds

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