Udo Oppermann

NIHR Oxford Biomedical Research, Oxford, England, United Kingdom

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Publications (207)1100.95 Total impact

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    ABSTRACT: We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.
    No preview · Article · Jan 2016 · Journal of Medicinal Chemistry
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    ABSTRACT: Development of tool molecules that inhibit Jumonji demethylases allows for the investigation of cancer-associated transcription. While scaffolds such as 2,4-pyridinedicarboxylic acid (2,4-PDCA) are potent inhibitors, they exhibit limited selectivity. To discover new inhibitors for the KDM4 demethylases, enzymes overexpressed in several cancers, we docked a library of 600 000 fragments into the high-resolution structure of KDM4A. Among the most interesting chemotypes were the 5-aminosalicylates, which docked in two distinct but overlapping orientations. Docking poses informed the design of covalently linked fragment compounds, which were further derivatized. This combined approach improved affinity by ∼3 log-orders to yield compound 35 (Ki = 43 nM). Several hybrid inhibitors were selective for KDM4C over the related enzymes FIH, KDM2A, and KDM6B while lacking selectivity against the KDM3 and KDM5 subfamilies. Cocrystal structures corroborated the docking predictions. This study extends the use of structure-based docking from fragment discovery to fragment linking optimization, yielding novel KDM4 inhibitors.
    No preview · Article · Dec 2015 · Journal of Medicinal Chemistry
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    ABSTRACT: Improved understanding of the role of inflammation in tendon disease is required to facilitate therapeutic target discovery. We studied supraspinatus tendons from patients experiencing pain before and after surgical subacromial decompression treatment. Tendons were classified as having early, intermediate, or advanced disease, and inflammation was characterized through activation of pathways mediated by interferon (IFN), nuclear factor kappa B (NF-kappa B), glucocorticoid receptor, and signal transducer and activator of transcription 6 (STAT-6). Inflammation signatures revealed expression of genes and proteins induced by IFN and NF-kappa B in early-stage disease and genes and proteins induced by STAT-6 and glucocorticoid receptor activation in advanced-stage disease. The proresolving proteins FPR2/ALX and ChemR23 were increased in early-stage disease compared to intermediate- to advanced-stage disease. Patients who were pain-free after treatment had tendons with increased expression of CD206 and ALOX15 mRNA compared to tendons from patients who continued to experience pain after treatment, suggesting that these genes and their pathways may moderate tendon pain. Stromal cells from diseased tendons cultured in vitro showed increased expression of NF-kappa B and IFN target genes after treatment with lipopolysaccharide or IFN gamma compared to stromal cells derived from healthy tendons. We identified 15-epi lipoxin A(4), a stable lipoxin isoform derived from aspirin treatment, as potentially beneficial in the resolution of tendon inflammation.
    Full-text · Article · Oct 2015 · Science translational medicine
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    ABSTRACT: Farnesyl pyrophosphate synthase (FPPS) is the major molecular target of nitrogen-containing bisphosphonates (N-BPs), used clinically as bone resorption inhibitors. We investigated the role of threonine 201 (Thr201) and tyrosine 204 (Tyr204) residues in substrate binding, catalysis and inhibition by N-BPs, employing kinetic and crystallographic studies of mutated FPPS proteins. Mutants of Thr201 illustrated the importance of the methyl group in aiding the formation of the Isopentenyl pyrophosphate (IPP) binding site, while Tyr204 mutations revealed the unknown role of this residue in both catalysis and IPP binding. The interaction between Thr201 and the side chain nitrogen of N-BP was shown to be important for tight binding inhibition by zoledronate (ZOL) and risedronate (RIS), although RIS was also still capable of interacting with the main-chain carbonyl of Lys200. The interaction of RIS with the phenyl ring of Tyr204 proved essential for the maintenance of the isomerized enzyme-inhibitor complex. Studies with conformationally restricted analogues of RIS reaffirmed the importance of Thr201 in the formation of hydrogen bonds with N-BPs. In conclusion we have identified new features of FPPS inhibition by N-BPs and revealed unknown roles of the active site residues in catalysis and substrate binding. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Aug 2015 · Bone
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    Adam Cribbs · Marc Feldmann · Udo Oppermann
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    ABSTRACT: The term 'epigenetics' loosely describes DNA-templated processes leading to heritable changes in gene activity and expression, which are independent of the underlying DNA sequence. Epigenetic mechanisms comprise of post-translational modifications of chromatin, methylation of DNA, nucleosome positioning as well as expression of noncoding RNAs. Major advances in understanding the role of DNA methylation in regulating chromatin functions have been made over the past decade, and point to a role of this epigenetic mechanism in human disease. Rheumatoid arthritis (RA) is an autoimmune disorder where altered DNA methylation patterns have been identified in a number of different disease-relevant cell types. However, the contribution of DNA methylation changes to RA disease pathogenesis is at present poorly understood and in need of further investigation. Here we review the current knowledge regarding the role of DNA methylation in rheumatoid arthritis and indicate its potential therapeutic implications.
    Full-text · Article · Aug 2015 · Therapeutic advances in musculoskeletal disease
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    ABSTRACT: Aldehyde dehydrogenases (ALDHs) metabolize reactive aldehydes and possess important physiological and toxicological functions in areas such as CNS, metabolic disorders, and cancers. Increased ALDH (e.g., ALDH1A1) gene expression and catalytic activity are vital biomarkers in a number of malignancies and cancer stem cells, highlighting the need for the identification and development of small molecule ALDH inhibitors. A new series of theophylline-based analogs as potent ALDH1A1 inhibitors is described. The optimization of hits identified from a quantitative high throughput screening (qHTS) campaign led to analogs with improved potency and early ADME properties. This chemotype exhibits highly selective inhibition against ALDH1A1 over ALDH3A1, ALDH1B1, and ALDH2 isozymes as well as other dehydrogenases such as HPGD and HSD17β4. Moreover, the pharmacokinetic evaluation of selected analog 64 (NCT-501) is also highlighted.
    No preview · Article · Jul 2015 · Journal of Medicinal Chemistry
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    ABSTRACT: The Structural Genomics Consortium (SGC) and its clinical, industry and disease-foundation partners are launching open-source preclinical translational medicine studies.
    Full-text · Article · Mar 2015 · Nature Reviews Drug Discovery

  • No preview · Conference Paper · Feb 2015
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    ABSTRACT: Dentine matrix protein 1 (DMP-1) is a non-collagenous matrix protein found in dentine and bone. It is highly expressed by osteocytes and has been identified in primary benign and malignant osteogenic bone tumours. Bone formation and matrix mineralisation are seen in a variety of benign and malignant soft tissue tumours and tumour-like lesions, and in this study, we analysed immunohistochemically the DMP-1 expression in a wide range of soft tissue lesions (n = 254) in order to assess whether DMP-1 expression is useful in the histological diagnosis of soft tissue tumours. Matrix staining of DMP-1 was seen in all cases of myositis ossificans, fibro-osseous tumour of the digits, extraskeletal soft tissue osteosarcoma and in most cases of ossifying fibromyxoid tumour. DMP-1 was also noted in dense collagenous connective tissue of mineralising soft tissue lesions such as tumoural calcinosis, dermatomyositis and calcific tendinitis. DMP-1 was expressed in areas of focal ossification and calcification in synovial sarcoma and other soft tissue tumours. With few exceptions, DMP-1 was not expressed in other benign and malignant soft tissue tumours. Our findings indicate that DMP-1 is a matrix marker of bone formation and mineralisation in soft tissue tumours. DMP-1 expression should be particularly useful in distinguishing extraskeletal osteosarcoma and ossifying fibromyxoid tumour from other sarcomas and in identifying areas of osteoid/bone formation and mineralisation in soft tissue tumours.
    No preview · Article · Jan 2015 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
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    ABSTRACT: Prostaglandins (PGs) are lipid compounds derived from arachidonic acid by the action of cyclooxygenases, acting locally as messenger molecules in a wide variety of physiological processes, such as inflammation, cell survival, apoptosis, smooth muscle contraction, adipocyte differentiation, vasodilation and platelet aggregation inhibition. In the inactivating pathway of PGs, the first metabolic intermediates are 15-keto-PGs, which are further converted into 13,14-dihydro-15-keto-PGs by different enzymes having 15-keto-PG reductase activity. Three human PG reductases (PGR), zinc-independent members of the medium-chain dehydrogenase/reductase (MDR) superfamily, perform the first irreversible step of the degradation pathway. We have focused on the characterization of the recombinant human enzyme prostaglandin reductase 1 (PGR1), also known as leukotriene B4 dehydrogenase. Only a partial characterization of this enzyme, isolated from human placenta, had been previously reported. In the present work, we have developed a new HPLC-based method for the determination of the 15-keto-PG reductase activity. We have performed an extensive kinetic characterization of PGR1, which catalyzes the NADPH-dependent reduction of α,β-double bond of aliphatic and aromatic aldehydes and ketones, and 15-keto-PGs. PGR1 also shows low activity in the oxidation of leukotriene B4. The best substrates in terms of kcat/Km were 15-keto-PGE2, trans-3-nonen-2-one and trans-2-decenal. Molecular docking simulations, based on the three-dimensional structure of the human enzyme (PDB ID 2Y05), and site-directed mutagenesis studies were performed to pinpoint important structural determinants, highlighting the role of Arg56 and Tyr245 in 15-keto-PG binding. Finally, inhibition analysis was done using non-steroidal anti-inflammatory drugs (NSAIDs) as potential inhibitors. Copyright © 2015. Published by Elsevier Ireland Ltd.
    No preview · Article · Jan 2015 · Chemico-Biological Interactions
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    ABSTRACT: Short-chain dehydrogenases/reductases (SDRs) constitute a large, functionally diverse branch of enzymes within the class of NAD(P)(H) dependent oxidoreductases. In humans, over 80 genes have been identified with distinct metabolic roles in carbohydrate, amino acid, lipid, retinoid and steroid hormone metabolism, frequently associated with inherited genetic defects. Besides metabolic functions, a subset of atypical SDR proteins appears to play critical roles in adapting to redox status or RNA processing, and thereby controlling metabolic pathways.
    No preview · Article · Dec 2014 · Chemico-Biological Interactions
  • X Cheng · E S Hookway · T Kashima · U Oppermann · A Galione · N A Athanasou
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    ABSTRACT: Osteoclasts are specialised bone resorbing cells which form by fusion of circulating mononuclear phagocyte precursors. Bone resorption results in the release of large amounts of calcium into the extracellular fluid (ECF), but it is not certain whether changes in extracellular calcium concentration [Ca(2+)]e influence osteoclast formation and resorption. In this study, we sought to determine the effect of [Ca(2+)]e and NAADP, a potent calcium mobilising messenger that induces calcium uptake, on human osteoclast formation and resorption. CD14+ human monocytes were cultured with M-CSF and RANKL in the presence of different concentrations of calcium and NAADP and the effect on osteoclast formation and resorption evaluated. We found that the number of TRAP+ multinucleated cells and the extent of lacunar resorption were reduced when there was an increase in extracellular calcium and NAADP. This was associated with a decrease in RANK mRNA expression by CD14+ cells. At high concentrations (20 mM) of [Ca(2+)]e mature osteoclast resorption activity remained unaltered relative to control cultures. Our findings indicate that osteoclast formation is inhibited by a rise in [Ca(2+)]e and that RANK expression by mononuclear phagocyte osteoclast precursors is also [Ca(2+)]e dependent. Changes in NAADP also influence osteoclast formation, suggesting a role for this molecule in calcium handling. Osteoclasts remained capable of lacunar resorption, even at high ECF [Ca(2+)]e, in keeping with their role in physiological and pathological bone resorption.
    No preview · Article · Nov 2014 · Calcified Tissue International
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    ABSTRACT: Replying to B. Heinemann . Nature 514, http://dx.doi.org/10.1038/nature13688 (2014)We welcome the accompanying Comment by Heinemann et al., in which the authors use an extensive panel of sensitive KDM assays to independently confirm our results that GSK-J1 is a potent KDM6 inhibitor. Additionally, Heinemann et al. demonstrate that GSK-J1 has some, albeit weaker, activity towards KDM5B and KDM5C, for which we only had preliminary data available at the time of our original publication. As our jumonji assay portfolio expands, we have continued to update the GSK-J1 activity profile on the SGC website (http://www.thesgc.org/chemical-probes/GSKJ1); this includes KDM5 inhibition activity by GSK-J1 similar to that reported by Heinemann. In conclusion, GSK-J1 remains the most selective KDM inhibitor yet disclosed and thus a valuable chemical tool.
    No preview · Article · Oct 2014 · Nature
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    ABSTRACT: Post-translational modifications play diverse biological functions. Hydroxylation of collagen proteins has long been a recognised post-translational modification in eukaryotes. In the case of collagen, hydroxylation of prolyl residues, by 2-oxoglutarate and iron dependent enzymes (2OG oxygenases), in collagen proteins allows for the stabilisation of the collagen triple helix structure through conformational restraint and through the addition of a hydrogen bond donor. Additionally, hydroxylation of lysine side chains of collagen is required for cross-linking collagen (and possibly other proteins) in the extra-cellular matrix. Post-translational prolyl hydroxylation also plays a pivotal role in transcriptional regulation of the hypoxic response, as catalyzed by the hypoxia inducible factor / HIF prolyl hydroxylases (PHDs or EGLN enzymes). Recently, ribosomal protein hydroxylation catalyzed by 2OG- and Fe(II)-dependent oxygenases has been found to be a highly conserved post-translational modification in eukaryotes and prokaryotes (Ge et al and Loenarz et al). We present several crystal structures of 2OG oxygenases involved in ribosomal protein hydroxylation.
    Full-text · Article · Aug 2014 · Acta Crystallographica Section A: Foundations and Advances
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    ABSTRACT: The JmjC domain-containing proteins are hydroxylases that confer posttranslational modifications on histone tails, by removing methylation marks on methylated lysine residues. This serves to either promote or repress gene transcription. The JMJD2A-D family members include the enzyme Jumonji domain 2C (JMJD2C), which specifically demethylates di- and trimethylated histone H3 at Lys 9 or Lys 36.[1] Dysregulation of JMJD2C has been implicated in prostate, colonic, and breast cancer as the demethylase can modify the expression levels of oncogenes.[2] The goal of the present study was to identify potent and selective small-molecule inhibitors of JMJD2C, to be used as chemical biology tools to further investigate the role of JMJD2C in cell proliferation and survival. Using high-resolution crystal structures of the JMJD2 subfamily members as templates, we have performed a small molecule virtual docking screen. From the ~3 million molecules that were docked, this experiment identified 21 compounds as possible leads. These compounds were tested against JMJD2C in enzymatic assays and here we report an overall hit rate of 76%, with 8 compounds demonstrating an IC50 of 176μM to 1.18μM. A molecule containing a salicylate core was selected as a candidate for optimization and thus far we have completed several rounds of iterative target-specific compound docking, hybrid molecule design, compound synthesis and in vitro characterization. Notably, our method demonstrated a substantial increase in potency when we linked two docked fragments together and further derivatized this new scaffold, through which we have successfully derived a 65nM inhibitor of JMJD2C. A compound representing the inhibitor scaffold has been co-crystallized with JMJD2A to a resolution of 2.4 Å. In the crystal structure each asymmetric unit contains two JMJD2A monomers, each bound to a single inhibitor molecule. This complex-structure superposes well with the docked pose for the hybrid series of compounds. We are now focusing our efforts on identifying an inhibitor that is selective for the JMJD2 family over other JmjC domain-containing proteins.
    Preview · Article · Aug 2014 · Acta Crystallographica Section A: Foundations and Advances
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    ABSTRACT: The retinoblastoma tumor suppressor protein pRb is a key regulator of cell cycle progression and mediator of the DNA damage response. Lysine methylation at K810, which occurs within a critical Cdk phosphorylation motif, holds pRb in the hypophosphorylated growth-suppressing state. We show here that methyl K810 is read by the tandem tudor domain containing tumor protein p53 binding protein 1 (53BP1). Structural elucidation of 53BP1 in complex with a methylated K810 pRb peptide emphasized the role of the 53BP1 tandem tudor domain in recognition of the methylated lysine and surrounding residues. Significantly, binding of 53BP1 to methyl K810 occurs on E2 promoter binding factor target genes and allows pRb activity to be effectively integrated with the DNA damage response. Our results widen the repertoire of cellular targets for 53BP1 and suggest a previously unidentified role for 53BP1 in regulating pRb tumor suppressor activity.
    Full-text · Article · Jul 2014 · Proceedings of the National Academy of Sciences
  • K. Rooke · L. Kruidenier · H. Che · P. Mander · C. Swales · R. Prinjha · U. Oppermann
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    ABSTRACT: Background Macrophages are central players in the pathogenesis of rheumatoid arthritis, and targeted inhibition of their principal cytokine products, TNFα and IL-6, are effective treatments. However, a significant proportion of patients still fail to respond to current therapies, and there is a continuing need for new therapeutic targets. Epigenetic modifications are increasingly recognised as key pathogenic features of RA and therefore inhibition of epigenetic anomalies has been identified as a potential future therapeutic strategy. Objectives This study used small molecule inhibitors to identify epigenetic factors that mediate macrophage-derived pro-inflammatory cytokine production from healthy donors and patients with RA. Methods Peripheral blood monocytes (PBMCs) were isolated from 10 healthy donors and 3 patients with rheumatoid arthritis; synovial fluid (SF) macrophages were also derived from the RA patients following therapeutic arthrocentesis. All patients were recruited from the Nuffield Orthopaedic Centre and gave written informed consent. PBMCs were differentiated into macrophages and stimulated with lipopolysaccharide (LPS) as a model of inflammation. PBMC and SF-derived macrophages were then treated with a panel of small molecule bromodomain, demethylase and deacetylase inhibitors to assess the impact of chromatin modification on macrophage pro-inflammatory cytokine production, including TNFα and IL-6. Cytokine production was detected by multiplex ELISA and supported by q-PCR data. Cell viability was determined using a WST-1 assay. Results Macrophages from healthy volunteers and patients with RA responded differently to the tested epigenetic inhibitors. Bromodomain (PFI-1, (+)-JQ1 and I-BET), demethylase (GSK-J4) and deacetylase (SAHA and CXD101) inhibitors all significantly reduced the production of TNFα and IL-6 from healthy donor PBMC-derived macrophages. The bromodomain and demethylase inhibitors effectively inhibited cytokine production from the PBMCs of patients with RA, but of the deacetylase inhibitors tested, only SAHA had significant effect. In addition, cytokine production from RA SF-derived macrophages was significantly reduced by the bromodomain inhibitors and SAHA-mediated deacetylase inhibition, but there was no significant effect with demethylase inhibition. Conclusions Differential responses to epigenetic inhibitors may represent differences in epigenetic modifications or mechanisms between healthy and RA macrophages. Further investigation into these differences, as well as specific mechanistic effects of epigenetic inhibitors, could lead to a clearer understanding of disease pathogenesis and help to identify novel therapeutic targets. Acknowledgements This work was generously funded by BBSRC and GSK Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4218
    No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: 2-Oxoglutarate (2OG)-dependent oxygenases have important roles in the regulation of gene expression via demethylation of N-methylated chromatin components and in the hydroxylation of transcription factors and splicing factor proteins. Recently, 2OG-dependent oxygenases that catalyse hydroxylation of transfer RNA and ribosomal proteins have been shown to be important in translation relating to cellular growth, TH17-cell differentiation and translational accuracy. The finding that ribosomal oxygenases (ROXs) occur in organisms ranging from prokaryotes to humans raises questions as to their structural and evolutionary relationships. In Escherichia coli, YcfD catalyses arginine hydroxylation in the ribosomal protein L16; in humans, MYC-induced nuclear antigen (MINA53; also known as MINA) and nucleolar protein 66 (NO66) catalyse histidine hydroxylation in the ribosomal proteins RPL27A and RPL8, respectively. The functional assignments of ROXs open therapeutic possibilities via either ROX inhibition or targeting of differentially modified ribosomes. Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. Comparison of ROX crystal structures with those of other JmjC-domain-containing hydroxylases, including the hypoxia-inducible factor asparaginyl hydroxylase FIH and histone N(ε)-methyl lysine demethylases, identifies branch points in 2OG-dependent oxygenase evolution and distinguishes between JmjC-containing hydroxylases and demethylases catalysing modifications of translational and transcriptional machinery. The structures reveal that new protein hydroxylation activities can evolve by changing the coordination position from which the iron-bound substrate-oxidizing species reacts. This coordination flexibility has probably contributed to the evolution of the wide range of reactions catalysed by oxygenases.
    Full-text · Article · May 2014 · Nature
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    ABSTRACT: The Jumonji C lysine demethylases (KDMs) are 2-oxoglutarate- and Fe(II)-dependent oxygenases. KDM6A (UTX) and KDM6B (JMJD3) are KDM6 subfamily members that catalyze demethylation of Nϵ-methylated histone 3 lysine 27 (H3K27), a mark important for transcriptional repression. Despite reports stating that UTY(KDM6C) is inactive as a KDM, we demonstrate by biochemical studies, employing MS and NMR, that UTY(KDM6C) is an active KDM. Crystallographic analyses reveal that the UTY(KDM6C) active site is highly conserved with those of KDM6B and KDM6A. UTY(KDM6C) catalyzes demethylation of H3K27 peptides in vitro, analogously to KDM6B and KDM6A, but with reduced activity, due to point substitutions involved in substrate binding. The results expand the set of human KDMs and will be of use in developing selective KDM inhibitors.
    Preview · Article · May 2014 · Journal of Biological Chemistry
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    S. J. B. Snelling · A. Kramm · C. Yapp · A. J. Carr · U. Oppermann

    Full-text · Article · Apr 2014 · Osteoarthritis and Cartilage

Publication Stats

8k Citations
1,100.95 Total Impact Points

Institutions

  • 2008-2015
    • NIHR Oxford Biomedical Research
      Oxford, England, United Kingdom
  • 2005-2015
    • University of Oxford
      • Structural Genomics Consortium (SGC)
      Oxford, England, United Kingdom
  • 2011
    • University of Bristol
      • School of Biochemistry
      Bristol, England, United Kingdom
  • 2010
    • University of Toronto
      • Structural Genomics Consortium
      Toronto, Ontario, Canada
    • The University of Sheffield
      Sheffield, England, United Kingdom
  • 1996-2008
    • Karolinska Institutet
      • Department of Medical Biochemistry and Biophysics
      Solna, Stockholm, Sweden
  • 1992-1993
    • Philipps University of Marburg
      • Institute for Physiological Chemistry
      Marburg, Hesse, Germany