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Small molecule epigenetics

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https://www.readbyqxmd.com/read/28092669/interplay-between-epigenetics-and-metabolism-in-oncogenesis-mechanisms-and-therapeutic-approaches
#1
REVIEW
C C Wong, Y Qian, J Yu
Epigenetic and metabolic alterations in cancer cells are highly intertwined. Oncogene-driven metabolic rewiring modifies the epigenetic landscape via modulating the activities of DNA and histone modification enzymes at the metabolite level. Conversely, epigenetic mechanisms regulate the expression of metabolic genes, thereby altering the metabolome. Epigenetic-metabolomic interplay has a critical role in tumourigenesis by coordinately sustaining cell proliferation, metastasis and pluripotency. Understanding the link between epigenetics and metabolism could unravel novel molecular targets, whose intervention may lead to improvements in cancer treatment...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28080202/chemical-probes-targeting-epigenetic-proteins-applications-beyond-oncology
#2
Suzanne Ackloo, Peter J Brown, Susanne Müller
Epigenetic chemical probes are potent, cell-active, small molecule inhibitors and antagonists of specific domains in a protein; they have been indispensable for studying bromodomains and protein methyltransferases. The Structural Genomics Consortium (SGC), comprising scientists from academic and pharmaceutical laboratories, has generated most of the current epigenetic chemical probes. Moreover, the SGC has shared about four thousand aliquots of these probes, which have been used primarily for phenotypic profiling or to validate targets in cell lines or primary patient samples cultured in vitro...
January 12, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28071961/cellular-analysis-of-the-action-of-epigenetics-drugs-and-probes
#3
Mirjam Hau, Fides Zenk, A Ganesan, Nicola Iovino, Manfred Jung
Small molecule drugs and probes are important tools in drug discovery, pharmacology, and cell biology. This is of course also true for epigenetic inhibitors. Important examples for the use of established epigenetic inhibitors are the study of the mechanistic role of a certain target in a cellular setting or the modulation of a certain phenotype in an approach that aims towards therapeutic application. Alternatively, cellular testing may aim at the validation of a new epigenetic inhibitor in drug discovery approaches...
January 10, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28069948/genomic-targeting-of-epigenetic-probes-using-a-chemically-tailored-cas9-system
#4
Glen P Liszczak, Zachary Z Brown, Samuel H Kim, Rob C Oslund, Yael David, Tom W Muir
Recent advances in the field of programmable DNA-binding proteins have led to the development of facile methods for genomic localization of genetically encodable entities. Despite the extensive utility of these tools, locus-specific delivery of synthetic molecules remains limited by a lack of adequate technologies. Here we combine the flexibility of chemical synthesis with the specificity of a programmable DNA-binding protein by using protein trans-splicing to ligate synthetic elements to a nuclease-deficient Cas9 (dCas9) in vitro and subsequently deliver the dCas9 cargo to live cells...
January 9, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28038447/proteome-alterations-associated-with-transformation-of-multiple-myeloma-to-secondary-plasma-cell-leukemia
#5
Alexey Zatula, Aida Dikic, Celine Mulder, Animesh Sharma, Cathrine B Vågbø, Mirta M L Sousa, Anders Waage, Geir Slupphaug
Plasma cell leukemia is a rare and aggressive plasma cell neoplasm that may either originate de novo (primary PCL) or by leukemic transformation of multiple myeloma (MM) to secondary PCL (sPCL). The prognosis of sPCL is very poor, and currently no standard treatment is available due to lack of prospective clinical studies. In an attempt to elucidate factors contributing to transformation, we have performed super-SILAC quantitative proteome profiling of malignant plasma cells collected from the same patient at both the MM and sPCL stages of the disease...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/28032018/a-multi-target-small-molecule-for-targeted-transcriptional-activation-of-therapeutically-significant-nervous-system-genes
#6
Yulei Wei, Ganesh N Pandian, Tingting Zou, Junichi Taniguchi, Shinsuke Sato, Gengo Kashiwazaki, Thangavel Vaijayanthi, Takuya Hidaka, Toshikazu Bando, Hiroshi Sugiyama
An integrated multi-target small molecule capable of altering dynamic epigenetic and transcription programs associated with the brain and nervous system has versatile applications in the regulation of therapeutic and cell-fate genes. Recently, we have been constructing targeted epigenetic ON switches by integrating sequence-specific DNA binding pyrrole-imidazole polyamides with a potent histone deacetylase inhibitor SAHA. Here, we identified a DNA-based epigenetic ON switch termed SAHA-L as the first-ever multi-target small molecule capable of inducing transcription programs associated with the human neural system and brain synapses networks in BJ human foreskin fibroblasts and 201B7-iPS cells...
December 2016: ChemistryOpen
https://www.readbyqxmd.com/read/28024084/targeting-the-histone-methyltransferase-g9a-activates-imprinted-genes-and-improves-survival-of-a-mouse-model-of-prader-willi-syndrome
#7
Yuna Kim, Hyeong-Min Lee, Yan Xiong, Noah Sciaky, Samuel W Hulbert, Xinyu Cao, Jeffrey I Everitt, Jian Jin, Bryan L Roth, Yong-Hui Jiang
Prader-Willi syndrome (PWS) is an imprinting disorder caused by a deficiency of paternally expressed gene(s) in the 15q11-q13 chromosomal region. The regulation of imprinted gene expression in this region is coordinated by an imprinting center (PWS-IC). In individuals with PWS, genes responsible for PWS on the maternal chromosome are present, but repressed epigenetically, which provides an opportunity for the use of epigenetic therapy to restore expression from the maternal copies of PWS-associated genes. Through a high-content screen (HCS) of >9,000 small molecules, we discovered that UNC0638 and UNC0642-two selective inhibitors of euchromatic histone lysine N-methyltransferase-2 (EHMT2, also known as G9a)-activated the maternal (m) copy of candidate genes underlying PWS, including the SnoRNA cluster SNORD116, in cells from humans with PWS and also from a mouse model of PWS carrying a paternal (p) deletion from small nuclear ribonucleoprotein N (Snrpn (S)) to ubiquitin protein ligase E3A (Ube3a (U)) (mouse model referred to hereafter as m(+)/p(ΔS-U))...
December 26, 2016: Nature Medicine
https://www.readbyqxmd.com/read/28019723/therapeutical-potential-of-deregulated-lysine-methyltransferase-smyd3-as-a-safe-target-for-novel-anticancer-agents
#8
Gurukumari Rajajeyabalachandran, Swetha Kumar, Thanabal Murugesan, Shanthi Ekambaram, Ramya Padmavathy, Sooriya Kumar Jegatheesan, Ramesh Mullangi, Sriram Rajagopal
SET and MYND domain containing-3 (SMYD3) is a member of the lysine methyltransferase family of proteins, and plays an important role in the methylation of various histone and non-histone targets. Proper functioning of SMYD3 is very important for the target molecules to determine their different roles in chromatin remodeling, signal transduction and cell cycle control. Due to the abnormal expression of SMYD3 in tumors, it is projected as a prognostic marker in various solid cancers. Areas covered: Here we elaborate on the general information, structure and the pathological role of SMYD3 protein...
December 26, 2016: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28018344/adjunct-strategies-for-tuberculosis-vaccines-modulating-key-immune-cell-regulatory-mechanisms-to-potentiate-vaccination
#9
REVIEW
Lakshmi Jayashankar, Richard Hafner
Tuberculosis (TB) remains a global health threat of alarming proportions, resulting in 1.5 million deaths worldwide. The only available licensed vaccine, Bacillus Calmette-Guérin, does not confer lifelong protection against active TB. To date, development of an effective vaccine against TB has proven to be elusive, and devising newer approaches for improved vaccination outcomes is an essential goal. Insights gained over the last several years have revealed multiple mechanisms of immune manipulation by Mycobacterium tuberculosis (Mtb) in infected macrophages and dendritic cells that support disease progression and block development of protective immunity...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/28011470/advances-in-experimental-targeted-therapy-and-immunotherapy-for-patients-with-glioblastoma-multiforme
#10
REVIEW
Jiri Polivka, Jiri Polivka, Lubos Holubec, Tereza Kubikova, Vladimir Priban, Ondrej Hes, Kristyna Pivovarcikova, Inka Treskova
Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor in adults with generally dismal prognosis, early clinical deterioration and high mortality. GBM is extremely invasive, characterized by intense and aberrant vascularization and high resistance to multimodal treatment. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) has very limited effectiveness, with median overall survival of patients no longer than 15 months. Progress in genetics and epigenetics of GBM over the past decade has revealed various aberrations in cellular signaling pathways, the tumor microenvironment, and pathological angiogenesis...
2017: Anticancer Research
https://www.readbyqxmd.com/read/27992714/structure-guided-design-of-eed-binders-allosterically-inhibiting-the-epigenetic-polycomb-repressive-complex-2-prc2-methyltransferase
#11
Andreas Lingel, Martin Sendzik, Ying Huang, Michael D Shultz, John Cantwell, Michael P Dillon, Xingnian Fu, John Fuller, Tobias Gabriel, Justin Gu, Xiangqing Jiang, Ling Li, Fang Liang, Maureen McKenna, Wei Qi, Weijun Rao, Xijun Sheng, Wei Shu, James Sutton, Benjamin Taft, Long Wang, Jue Zeng, Hailong Zhang, Maya Zhang, Kehao Zhao, Mika Lindvall, Dirksen E Bussiere
PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 of histone H3, leading to chromatin compaction and repression of tumor suppressor genes. Inhibiting this activity by small molecules targeting EZH2 was shown to result in antitumor efficacy. Here, we describe the optimization of a chemical series representing a new class of PRC2 inhibitors which acts allosterically via the trimethyllysine pocket of the noncatalytic EED subunit...
January 3, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27990121/targeting-mechanotransduction-at-the-transcriptional-level-yap-and-brd4-are-novel-therapeutic-targets-for-the-reversal-of-liver-fibrosis
#12
REVIEW
Altynbek Zhubanchaliyev, Aibar Temirbekuly, Kuralay Kongrtay, Leah C Wanshura, Jeannette Kunz
Liver fibrosis is the result of a deregulated wound healing process characterized by the excessive deposition of extracellular matrix. Hepatic stellate cells (HSCs), which are activated in response to liver injury, are the major source of extracellular matrix and drive the wound healing process. However, chronic liver damage leads to perpetual HSC activation, progressive formation of pathological scar tissue and ultimately, cirrhosis and organ failure. HSC activation is triggered largely in response to mechanosignaling from the microenvironment, which induces a profibrotic nuclear transcription program that promotes HSC proliferation and extracellular matrix secretion thereby setting up a positive feedback loop leading to matrix stiffening and self-sustained, pathological, HSC activation...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27986499/targeting-chromatin-aging-the-epigenetic-impact-of-longevity-associated-interventions
#13
Adam E Field, Peter D Adams
A rapidly growing body of evidence has shown that chromatin undergoes radical alterations as an organism ages, but how these changes relate to aging itself is an open question. It is likely that these processes contribute to genomic instability and loss of transcriptional fidelity, which in turn drives deleterious age-related phenotypes. Interventions associated with increased healthspan and longevity such as reduced insulin/IGF signalling (IIS), inhibition of mTOR and energy depletion resulting in SIRT1/AMPK activation, all have beneficial effects which ameliorate multiple facets of age-associated decline...
December 13, 2016: Experimental Gerontology
https://www.readbyqxmd.com/read/27980707/a-fluorescence-polarization-biophysical-assay-for-the-naegleria-dna-hydroxylase-tet1
#14
Laura J Marholz, Wei Wang, Yu Zheng, Xiang Wang
The discovery of the 5-methylcytosine (5mC) oxidation by the ten-eleven translocation (Tet) protein family was an important advancement in our understanding of DNA-modified epigenetics. Potent inhibitors of these proteins are greatly desired for both the understanding of the functions of these enzymes and to serve as eventual therapeutic leads. So far, the discovery of such small molecules with high affinity has been quite limited. Original tools to screen for activity are greatly needed in order to accelerate this process...
February 11, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27973612/long-lasting-wnt-tcf-response-blocking-and-epigenetic-modifying-activities-of-withanolide-f-in-human-cancer-cells
#15
Chandan Seth, Christophe Mas, Arwen Conod, Jens Mueller, Karsten Siems, Monika Kuciak, Isabel Borges, Ariel Ruiz I Altaba
The WNT-TCF signaling pathway participates in adult tissue homeostasis and repair, and is hyperactive in a number of human diseases including cancers of the colon. Whereas to date there are no antagonists approved for patient use, a potential problem for their sustained use is the blockade of WNT signaling in healthy tissues, thus provoking potentially serious co-lateral damage. Here we have screened a library of plant and microorganism small molecules for novel WNT signaling antagonists and describe withanolide F as a potent WNT-TCF response blocker...
2016: PloS One
https://www.readbyqxmd.com/read/27943567/methyltransferase-directed-labeling-of-biomolecules-and-its-applications
#16
Jochem Deen, Charlotte Vranken, Volker Leen, Robert K Neely, Kris Pieter Frans Janssen, Johan Hofkens
Methyltransferases (MTases) compose a large family of enzymes which have the ability to methylate a diverse set of targets, ranging from the three major biopolymers DNA, RNA and protein to small molecules. Most of these MTases use the cofactor S-Adenosyl-L-Methionine (AdoMet) as their methyl source. Given the important biological role of methylation, e.g. in epigenetic regulation of gene activity and the vast potential of targeted functionalization in biology, diagnostics and nanotechnology, it should come as no surprise that recent years have seen significant efforts in the development of AdoMet analogues with the aim of transferring moieties other than simple methyl groups...
December 12, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27941949/in-vitro-effects-of-the-small-molecule-protein-kinase-c-agonists-on-hiv-latency-reactivation
#17
Jessica Brogdon, Widade Ziani, Xiaolei Wang, Ronald S Veazey, Huanbin Xu
The persistence of latently HIV-infected cellular reservoirs represents the major obstacle to virus eradication in patients under antiretroviral therapy (ART). Cure strategies to eliminate these reservoirs are thus needed to reactivate proviral gene expression in latently infected cells. In this study, we tested optimal concentrations of PKC agonist candidates (PEP005/Ingenol-3-angelate, prostratin, bryostatin-1, and JQ1) to reactivate HIV latency in vitro, and examined their effects on cell survival, activation and epigenetic histone methylation after treatment alone or in combination in cell line and isolated CD4 T cells from SIV-infected macaques...
December 12, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27935410/establishment-of-a-high-throughput-detection-system-for-dna-demethylating-agents
#18
Eriko Okochi-Takada, Naoko Hattori, Akihiro Ito, Tohru Niwa, Mika Wakabayashi, Kana Kimura, Minoru Yoshida, Toshikazu Ushijima
Epigenetic alterations underlie various human disorders, including cancer, and this has resulted in the development of drugs targeting epigenetic alterations. Although DNA demethylating agents are one of the major epigenetic drugs, only two compounds-5-azacytidine (5-aza-CR, azacitidine) and 5-aza-2'-deoxycytidine (5-aza-dC, decitabine)-have obtained clinical approval. Here, we aimed to establish a detection system for DNA demethylating agents suitable for a high-throughput screening (HTS) in mammalian cells...
December 9, 2016: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/27932495/modulations-of-sir-nucleosome-interactions-of-reconstructed-yeast-silent-pre-heterochromatin-by-o-acetyl-adp-ribose-and-magnesium
#19
Shu-Yun Tung, Sue-Hong Wang, Sue-Ping Lee, Shu-Ping Tsai, Hsiao-Hsuian Shen, Feng-Jung Chen, Yu-Yi Wu, Sheng-Pin Hsiao, Gunn-Guang Liou
To study epigenetic inheritance, yeast silent heterochromatin provides an excellent model. Previously, we developed an in vitro assembly system to demonstrate the formation of filament structures with requirements that mirror yeast epigenetic gene silencing in vivo However, the properties of these filaments have not been investigated in detail. Here, we show that the assembly system requires Sir2, Sir3, Sir4, nucleosomes and O-acetyl-ADP-ribose. We also demonstrate that all Sir proteins and nucleosomes are components of these filaments to prove they are SIR-nucleosome filaments...
December 8, 2016: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27930986/plant-derived-flavone-apigenin-the-small-molecule-with-promising-activity-against-therapeutically-resistant-prostate-cancer
#20
REVIEW
Shabir Ahmad Ganai
Prostate cancer is the second leading cause of cancer related deaths in men in the United States. Mounting evidences suggest that in the pathophysiology of prostate cancer epigenetic modifications play a considerable role. Histone deacetylases (HDACs) have strong crosstalk with prostate cancer progression as they regulate various genes meant for tumour suppression. HDACs are emerging as striking molecular targets for anticancer drugs and therapy as their aberrant expression has been implicated in several cancers...
January 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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