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Craig L Parfett, Daniel Desaulniers
An emerging vision for toxicity testing in the 21st century foresees in vitro assays assuming the leading role in testing for chemical hazards, including testing for carcinogenicity. Toxicity will be determined by monitoring key steps in functionally validated molecular pathways, using tests designed to reveal chemically-induced perturbations that lead to adverse phenotypic endpoints in cultured human cells. Risk assessments would subsequently be derived from the causal in vitro endpoints and concentration vs...
June 1, 2017: International Journal of Molecular Sciences
Jun Liang, Sharada Labadie, Birong Zhang, Daniel F Ortwine, Snahel Patel, Maia Vinogradova, James R Kiefer, Till Mauer, Victor S Gehling, Jean-Christophe Harmange, Richard Cummings, Tommy Lai, Jiangpeng Liao, Xiaoping Zheng, Yichin Liu, Amy Gustafson, Erica Van der Porten, Weifeng Mao, Bianca M Liederer, Gauri Deshmukh, Le An, Yingqing Ran, Marie Classon, Patrick Trojer, Peter S Dragovich, Lesley Murray
A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit...
May 5, 2017: Bioorganic & Medicinal Chemistry Letters
Jerzy Dorosz, Lars Olsen, Signe Teuber Seger, Cornelia Steinhauer, Giorgos Bouras, Charlotte Helgstrand, Anders Wiuf, Michael Gajhede
The histone demethylase PHF8 catalyzes demethylation of mono- and di-methylated Lys9 on histone H3 (H3K9me1/2), and is a transcriptional activator involved in the development and cancer. Affinity and specificity of PHF8 towards H3K9me2 is affected by interaction with both the catalytic domain and a PHD reader domain. The latter specifically recognizes tri-methylated Ly4 on histone H3. A fragment of the histone H3 tail with tri-methylated Lys4 was used as a template for the structure-based design of a cyclic, cell-penetrating peptide that exhibits micromolar binding affinity to PHF8 in biochemical assays...
April 21, 2017: Chembiochem: a European Journal of Chemical Biology
Anthony Tumber, Andrea Nuzzi, Edward S Hookway, Stephanie B Hatch, Srikannathasan Velupillai, Catrine Johansson, Akane Kawamura, Pavel Savitsky, Clarence Yapp, Aleksandra Szykowska, Na Wu, Chas Bountra, Claire Strain-Damerell, Nicola A Burgess-Brown, Gian Filippo Ruda, Oleg Fedorov, Shonagh Munro, Katherine S England, Radoslaw P Nowak, Christopher J Schofield, Nicholas B La Thangue, Charlotte Pawlyn, Faith Davies, Gareth Morgan, Nick Athanasou, Susanne Müller, Udo Oppermann, Paul E Brennan
Methylation 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 Fe(2+)-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...
March 16, 2017: Cell Chemical Biology
Lauren P Blair, Zongzhi Liu, Ramon Lorenzo D Labitigan, Lizhen Wu, Dinghai Zheng, Zheng Xia, Erica L Pearson, Fathima I Nazeer, Jian Cao, Sabine M Lang, Rachel J Rines, Samuel G Mackintosh, Claire L Moore, Wei Li, Bin Tian, Alan J Tackett, Qin Yan
The complexity by which cells regulate gene and protein expression is multifaceted and intricate. Regulation of 3' untranslated region (UTR) processing of mRNA has been shown to play a critical role in development and disease. However, the process by which cells select alternative mRNA forms is not well understood. We discovered that the Saccharomyces cerevisiae lysine demethylase, Jhd2 (also known as KDM5), recruits 3'UTR processing machinery and promotes alteration of 3'UTR length for some genes in a demethylase-dependent manner...
November 2016: Science Advances
Ann-Sofie B Brier, Anne Loft, Jesper G S Madsen, Thomas Rosengren, Ronni Nielsen, Søren F Schmidt, Zongzhi Liu, Qin Yan, Hinrich Gronemeyer, Susanne Mandrup
The KDM5 family of histone demethylases removes the H3K4 tri-methylation (H3K4me3) mark frequently found at promoter regions of actively transcribed genes and is therefore generally considered to contribute to corepression. In this study, we show that knockdown (KD) of all expressed members of the KDM5 family in white and brown preadipocytes leads to deregulated gene expression and blocks differentiation to mature adipocytes. KDM5 KD leads to a considerable increase in H3K4me3 at promoter regions; however, these changes in H3K4me3 have a limited effect on gene expression per se...
February 28, 2017: Nucleic Acids Research
Joyce Taylor-Papadimitriou, Joy Burchell
No abstract text is available yet for this article.
January 2017: Expert Opinion on Therapeutic Targets
Rob J W Arts, Boris Novakovic, Rob Ter Horst, Agostinho Carvalho, Siroon Bekkering, Ekta Lachmandas, Fernando Rodrigues, Ricardo Silvestre, Shih-Chin Cheng, Shuang-Yin Wang, Ehsan Habibi, Luís G Gonçalves, Inês Mesquita, Cristina Cunha, Arjan van Laarhoven, Frank L van de Veerdonk, David L Williams, Jos W M van der Meer, Colin Logie, Luke A O'Neill, Charles A Dinarello, Niels P Riksen, Reinout van Crevel, Clary Clish, Richard A Notebaart, Leo A B Joosten, Hendrik G Stunnenberg, Ramnik J Xavier, Mihai G Netea
Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases...
December 13, 2016: Cell Metabolism
Angela Hayes, N Yi Mok, Manjuan Liu, Ching Thai, Alan T Henley, Butrus Atrash, Rachel M Lanigan, Jemmy Sejberg, Yann-Vaï Le Bihan, Vassilios Bavetsias, Julian Blagg, Florence I Raynaud
1. We have previously described C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as cell permeable inhibitors of the KDM4 and KDM5 subfamilies of JmjC histone lysine demethylases. 2. Although exemplar compound 1 exhibited moderate clearance in mouse liver microsomes, it was highly cleared in vivo due to metabolism by aldehyde oxidase (AO). Similar human and mouse AO-mediated metabolism was observed with the pyrido[3,4-d]pyrimidin-4(3H)-one scaffold and other C8-substituted derivatives. 3. We identified the C2-position as the oxidation site by LC-MS and (1)H-NMR and showed that C2-substituted derivatives are no longer AO substrates...
October 26, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Yvonne C Lussi, Luca Mariani, Carsten Friis, Juhani Peltonen, Toshia R Myers, Claudia Krag, Garry Wong, Anna Elisabetta Salcini
Methylation of Histone 3 Lysine 4 (H3K4) is largely associated with promoters and enhancers of actively transcribed genes and it is finely regulated during development by the action of histone methyltransferases and demethylases. H3K4me3 demethylases of the KDM5 family have been previously implicated in development, but how the regulation of H3K4me3 level controls developmental processes is not fully established. Here, we show that the H3K4 demethylase RBR-2, the unique member of the KDM5 family in C. elegans, acts cell-autonomously and in a catalytic-dependent manner to control vulva precursor cells fate acquisition, by promoting the LIN-12/Notch pathway...
August 30, 2016: Development
Agnieszka Gacek-Matthews, Harald Berger, Takahiko Sasaki, Kathrin Wittstein, Clemens Gruber, Zachary A Lewis, Joseph Strauss
Histone posttranslational modifications (HPTMs) are involved in chromatin-based regulation of fungal secondary metabolite biosynthesis (SMB) in which the corresponding genes-usually physically linked in co-regulated clusters-are silenced under optimal physiological conditions (nutrient-rich) but are activated when nutrients are limiting. The exact molecular mechanisms by which HPTMs influence silencing and activation, however, are still to be better understood. Here we show by a combined approach of quantitative mass spectrometry (LC-MS/MS), genome-wide chromatin immunoprecipitation (ChIP-seq) and transcriptional network analysis (RNA-seq) that the core regions of silent A...
August 2016: PLoS Genetics
Sharada S Labadie, Peter S Dragovich, Richard T Cummings, Gauri Deshmukh, Amy Gustafson, Ning Han, Jean-Christophe Harmange, James R Kiefer, Yue Li, Jun Liang, Bianca M Liederer, Yichin Liu, Wanda Manieri, Wiefeng Mao, Lesley Murray, Daniel F Ortwine, Patrick Trojer, Erica VanderPorten, Maia Vinogradova, Li Wen
Features from a high throughput screening (HTS) hit and a previously reported scaffold were combined to generate 1,7-naphthyridones as novel KDM5 enzyme inhibitors with nanomolar potencies. These molecules exhibited high selectivity over the related KDM4C and KDM2B isoforms. An X-ray co-crystal structure of a representative molecule bound to KDM5A showed that these inhibitors are competitive with the co-substrate (2-oxoglutarate or 2-OG).
September 15, 2016: Bioorganic & Medicinal Chemistry Letters
Liudmila Zhaunova, Hiroyuki Ohkura, Manuel Breuer
During prophase of the first meiotic division (prophase I), chromatin dynamically reorganises to recombine and prepare for chromosome segregation. Histone modifying enzymes are major regulators of chromatin structure, but our knowledge of their roles in prophase I is still limited. Here we report on crucial roles of Kdm5/Lid, one of two histone demethylases in Drosophila that remove one of the trimethyl groups at Lys4 of Histone 3 (H3K4me3). In the absence of Kdm5/Lid, the synaptonemal complex was only partially formed and failed to be maintained along chromosome arms, while localisation of its components at centromeres was unaffected...
August 2016: PLoS Genetics
Victor S Gehling, Steven F Bellon, Jean-Christophe Harmange, Yves LeBlanc, Florence Poy, Shobu Odate, Shane Buker, Fei Lan, Shilpi Arora, Kaylyn E Williamson, Peter Sandy, Richard T Cummings, Christopher M Bailey, Louise Bergeron, Weifeng Mao, Amy Gustafson, Yichin Liu, Erica VanderPorten, James E Audia, Patrick Trojer, Brian K Albrecht
This communication describes the identification and optimization of a series of pan-KDM5 inhibitors derived from compound 1, a hit initially identified against KDM4C. Compound 1 was optimized to afford compound 20, a 10nM inhibitor of KDM5A. Compound 20 is highly selective for the KDM5 enzymes versus other histone lysine demethylases and demonstrates activity in a cellular assay measuring the increase in global histone 3 lysine 4 tri-methylation (H3K4me3). In addition compound 20 has good ADME properties, excellent mouse PK, and is a suitable starting point for further optimization...
September 1, 2016: Bioorganic & Medicinal Chemistry Letters
Dante Rotili, Andrea Mattevi
Histone lysine demethylase 5 enzymes (KDM5s) have recently been proposed as crucial oncogenic drivers. In this issue of Cell Chemical Biology, Horton et al. (2016) describe results of an extensive structural analysis that reveals how distinct inhibitor chemotypes bind KDM5 and suggest avenues for improving KDM5 inhibitory potency and selectivity.
July 21, 2016: Cell Chemical Biology
John R Horton, Xu Liu, Molly Gale, Lizhen Wu, John R Shanks, Xing Zhang, Philip J Webber, Joshua S K Bell, Stephen C Kales, Bryan T Mott, Ganesha Rai, Daniel J Jansen, Mark J Henderson, Daniel J Urban, Matthew D Hall, Anton Simeonov, David J Maloney, Margaret A Johns, Haian Fu, Ajit Jadhav, Paula M Vertino, Qin Yan, Xiaodong Cheng
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...
July 21, 2016: Cell Chemical Biology
Jun Liang, Birong Zhang, Sharada Labadie, Daniel F Ortwine, Maia Vinogradova, James R Kiefer, Victor S Gehling, Jean-Christophe Harmange, Richard Cummings, Tommy Lai, Jiangpeng Liao, Xiaoping Zheng, Yichin Liu, Amy Gustafson, Erica Van der Porten, Weifeng Mao, Bianca M Liederer, Gauri Deshmukh, Marie Classon, Patrick Trojer, Peter S Dragovich, Lesley Murray
Starting with a lead [1,5-a]pyrimidin-7(4H)-one-containing molecule (1), we generated potent, selective and orally bioavailable KDM5 inhibitors. Using structure- and property-based approaches, we designed 48 with improved cell potency (PC9 H3K4Me3 EC50=0.34μM). Furthermore, 48 maintained suitable physiochemical properties and displayed an excellent pharmacokinetic (PK) profile in mice. When dosed orally in mice at 50mg/kg twice a day (BID), 48 showed an unbound maximal plasma concentration (Cmax) >15-fold over its cell EC50, thereby providing a robust chemical probe for studying KDM5 biological functions in vivo...
August 15, 2016: Bioorganic & Medicinal Chemistry Letters
Catrine Johansson, Srikannathasan Velupillai, Anthony Tumber, Aleksandra Szykowska, Edward S Hookway, Radoslaw P Nowak, Claire Strain-Damerell, Carina Gileadi, Martin Philpott, Nicola Burgess-Brown, Na Wu, Jola Kopec, Andrea Nuzzi, Holger Steuber, Ursula Egner, Volker Badock, Shonagh Munro, Nicholas B LaThangue, Sue Westaway, Jack Brown, Nick Athanasou, Rab Prinjha, Paul E Brennan, Udo Oppermann
Members of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe(2+)-dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families...
July 2016: Nature Chemical Biology
Maia Vinogradova, Victor S Gehling, Amy Gustafson, Shilpi Arora, Charles A Tindell, Catherine Wilson, Kaylyn E Williamson, Gulfem D Guler, Pranoti Gangurde, Wanda Manieri, Jennifer Busby, E Megan Flynn, Fei Lan, Hyo-Jin Kim, Shobu Odate, Andrea G Cochran, Yichin Liu, Matthew Wongchenko, Yibin Yang, Tommy K Cheung, Tobias M Maile, Ted Lau, Michael Costa, Ganapati V Hegde, Erica Jackson, Robert Pitti, David Arnott, Christopher Bailey, Steve Bellon, Richard T Cummings, Brian K Albrecht, Jean-Christophe Harmange, James R Kiefer, Patrick Trojer, Marie Classon
The KDM5 family of histone demethylases catalyzes the demethylation of histone H3 on lysine 4 (H3K4) and is required for the survival of drug-tolerant persister cancer cells (DTPs). Here we report the discovery and characterization of the specific KDM5 inhibitor CPI-455. The crystal structure of KDM5A revealed the mechanism of inhibition of CPI-455 as well as the topological arrangements of protein domains that influence substrate binding. CPI-455 mediated KDM5 inhibition, elevated global levels of H3K4 trimethylation (H3K4me3) and decreased the number of DTPs in multiple cancer cell line models treated with standard chemotherapy or targeted agents...
July 2016: Nature Chemical Biology
Luca Mariani, Yvonne C Lussi, Julien Vandamme, Alba Riveiro, Anna Elisabetta Salcini
The dynamic regulation of histone modifications is important for modulating transcriptional programs during development. Aberrant H3K4 methylation is associated with neurological disorders, but how the levels and the recognition of this modification affect specific neuronal processes is unclear. Here, we show that RBR-2, the sole homolog of the KDM5 family of H3K4me3/2 demethylases in Caenorhabditis elegans, ensures correct axon guidance by controlling the expression of the actin regulator wsp-1. Loss of rbr-2 results in increased levels of H3K4me3 at the transcriptional start site of wsp-1, with concomitant higher wsp-1 expression responsible for defective axon guidance...
March 1, 2016: Development
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