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Angela Hayes, N Yi Mok, Manjuan Liu, Ching Thai, Alan T Henley, Butrus Atrash, Rachel M Lanigan, Jimmy 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...
September 12, 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
Vassilios Bavetsias, Rachel M Lanigan, Gian Filippo Ruda, Butrus Atrash, Mark G McLaughlin, Anthony Tumber, N Yi Mok, Yann-Vaï Le Bihan, Sally Dempster, Katherine J Boxall, Fiona Jeganathan, Stephanie B Hatch, Pavel Savitsky, Srikannathasan Velupillai, Tobias Krojer, Katherine S England, Jimmy Sejberg, Ching Thai, Adam Donovan, Akos Pal, Giuseppe Scozzafava, James M Bennett, Akane Kawamura, Catrine Johansson, Aleksandra Szykowska, Carina Gileadi, Nicola A Burgess-Brown, Frank von Delft, Udo Oppermann, Zoe Walters, Janet Shipley, Florence I Raynaud, Susan M Westaway, Rab K Prinjha, Oleg Fedorov, Rosemary Burke, Christopher J Schofield, Isaac M Westwood, Chas Bountra, Susanne Müller, Rob L M van Montfort, Paul E Brennan, Julian Blagg
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...
February 25, 2016: Journal of Medicinal Chemistry
Magdalena Korczynska, Daniel D Le, Noah Younger, Elisabet Gregori-Puigjané, Anthony Tumber, Tobias Krojer, Srikannathasan Velupillai, Carina Gileadi, Radosław P Nowak, Eriko Iwasa, Samuel B Pollock, Idelisse Ortiz Torres, Udo Oppermann, Brian K Shoichet, Danica Galonić Fujimori
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...
February 25, 2016: Journal of Medicinal Chemistry
Peter van Galen, Aaron D Viny, Oren Ram, Russell J H Ryan, Matthew J Cotton, Laura Donohue, Cem Sievers, Yotam Drier, Brian B Liau, Shawn M Gillespie, Kaitlin M Carroll, Michael B Cross, Ross L Levine, Bradley E Bernstein
Genome-wide profiling of histone modifications can provide systematic insight into the regulatory elements and programs engaged in a given cell type. However, conventional chromatin immunoprecipitation and sequencing (ChIP-seq) does not capture quantitative information on histone modification levels, requires large amounts of starting material, and involves tedious processing of each individual sample. Here, we address these limitations with a technology that leverages DNA barcoding to profile chromatin quantitatively and in multiplexed format...
January 7, 2016: Molecular Cell
Xingyin Liu, Julie Secombe
KDM5 family proteins are critically important transcriptional regulators whose physiological functions in the context of a whole animal remain largely unknown. Using genome-wide gene expression and binding analyses in Drosophila adults, we demonstrate that KDM5 (Lid) is a direct regulator of genes required for mitochondrial structure and function. Significantly, this occurs independently of KDM5's well-described JmjC domain-encoded histone demethylase activity. Instead, it requires the PHD motif of KDM5 that binds to histone H3 that is di- or trimethylated on lysine 4 (H3K4me2/3)...
December 15, 2015: Cell Reports
John R Horton, Amanda Engstrom, Elizabeth L Zoeller, Xu Liu, John R Shanks, Xing Zhang, Margaret A Johns, Paula M Vertino, Haian Fu, Xiaodong Cheng
The KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases remove methyl groups from tri- and dimethylated lysine 4 of histone H3. Accumulating evidence from primary tumors and model systems supports a role for KDM5A (JARID1A/RBP2) and KDM5B (JARID1B/PLU1) as oncogenic drivers. The KDM5 family is unique among the Jumonji domain-containing histone demethylases in that there is an atypical insertion of a DNA-binding ARID domain and a histone-binding PHD domain into the Jumonji domain, which separates the catalytic domain into two fragments (JmjN and JmjC)...
February 5, 2016: Journal of Biological Chemistry
Hélène Denis, Olivier Van Grembergen, Benjamin Delatte, Sarah Dedeurwaerder, Pascale Putmans, Emilie Calonne, Françoise Rothé, Christos Sotiriou, François Fuks, Rachel Deplus
MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Alteration of miRNA levels is common in tumors and contributes to the pathogenesis of human malignancies. In the present study we examined the role played by miR-137 in breast tumorigenesis. We found miR-137 levels to be lower in breast cancer cells than in their non-tumorigenic counterparts and observed reduced proliferation and migration of breast cancer cells overexpressing miR-137. We further identified KDM5B, a histone demethylase known to be involved in breast cancer tumorigenesis, as a target of miR-137...
February 2016: Molecular BioSystems
Anuja A George, Nancy C Walworth
Accurate chromosome segregation is necessary to ensure genomic integrity. Segregation depends on the proper functioning of the centromere, kinetochore, and mitotic spindle microtubules and is monitored by the spindle assembly checkpoint (SAC). In the fission yeast Schizosaccharomyces pombe, defects in Dis1, a microtubule-associated protein that influences microtubule dynamics, lead to mitotic arrest as a result of an active SAC and consequent failure to grow at low temperature. In a mutant dis1 background (dis1-288), loss of function of Msc1, a fission yeast homolog of the KDM5 family of proteins, suppresses the growth defect and promotes normal mitosis...
December 2015: Genetics
James R Davie, Wayne Xu, Genevieve P Delcuve
Histone H3 lysine 4 trimethylation (H3K4me3) is often stated as a mark of transcriptionally active promoters. However, closer study of the positioning of H3K4me3 shows the mark locating primarily after the first exon at the 5' splice site and overlapping with a CpG island in mammalian cells. There are several enzyme complexes that are involved in the placement of the H3K4me3 mark, including multiple protein complexes containing SETD1A, SETD1B, and MLL1 enzymes (writers). CXXC1, which is associated with SETD1A and SETD1B, target these enzymes to unmethylated CpG islands...
February 2016: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
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