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Small molecule epigenetics

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https://www.readbyqxmd.com/read/27911230/bromodomain-inhibitors-and-cancer-therapy-from-structures-to-applications
#1
Montserrat Pérez-Salvia, Manel Esteller
Aberrations in the epigenetic landscape are a hallmark of cancer. Alterations in enzymes that are "writers", "erasers", or "readers" of histone modification marks are common. Bromodomains are "readers" that bind acetylated lysines in histone tails. Their most important function is the regulation of gene transcription by the recruitment of different molecular partners. Moreover, proteins containing bromodomains are also epigenetic regulators, although little is known about the specific function of these domains...
December 2, 2016: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/27903272/inhibition-of-bromodomain-and-extra-terminal-bet-proteins-increases-nkg2d-ligand-mica-expression-and-sensitivity-to-nk-cell-mediated-cytotoxicity-in-multiple-myeloma-cells-role-of-cmyc-irf4-mir-125b-interplay
#2
Maria Pia Abruzzese, Maria Teresa Bilotta, Cinzia Fionda, Alessandra Zingoni, Alessandra Soriani, Elisabetta Vulpis, Cristiana Borrelli, Beatrice Zitti, Maria Teresa Petrucci, Maria Rosaria Ricciardi, Rosa Molfetta, Rossella Paolini, Angela Santoni, Marco Cippitelli
BACKGROUND: Anti-cancer immune responses may contribute to the control of tumors after conventional chemotherapy, and different observations have indicated that chemotherapeutic agents can induce immune responses resulting in cancer cell death and immune-stimulatory side effects. Increasing experimental and clinical evidence highlight the importance of natural killer (NK) cells in immune responses toward multiple myeloma (MM), and combination therapies able to enhance the activity of NK cells against MM are showing promise in treating this hematologic cancer...
December 1, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27897114/ureas-applications-in-drug-design-and-development
#3
Ajit Dhananjay Jagtap, Nagendra Bharatrao Kondekar, Amit A Sadani, Ji-Wang Chern
The unique hydrogen binding capabilities of ureas make them an important functional group to make drug-target interactions and thus incorporated in small molecules displaying broad range of bioactivities. The related research and numerous excellent achievements of ureas applicability in drug design for the modulation of selectivity, stability, toxicity and pharmacokinetic profile of lead molecules have become active topic. This review aims to provide insights in to the significance of urea in drug design by summarizing successful studies of various urea derivatives as modulators biological targets (viz...
November 29, 2016: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/27891192/the-quest-for-an-effective-and-safe-personalized-cell-therapy-using-epigenetic-tools
#4
REVIEW
T A L Brevini, G Pennarossa, E F M Manzoni, C E Gandolfi, A Zenobi, F Gandolfi
In the presence of different environmental cues that are able to trigger specific responses, a given genotype has the ability to originate a variety of different phenotypes. This property is defined as plasticity and allows cell fate definition and tissue specialization. Fundamental epigenetic mechanisms drive these modifications in gene expression and include DNA methylation, histone modifications, chromatin remodeling, and microRNAs. Understanding these mechanisms can provide powerful tools to switch cell phenotype and implement cell therapy...
2016: Clinical Epigenetics
https://www.readbyqxmd.com/read/27889451/diet-microbiota-interactions-mediate-global-epigenetic-programming-in-multiple-host-tissues
#5
Kimberly A Krautkramer, Julia H Kreznar, Kymberleigh A Romano, Eugenio I Vivas, Gregory A Barrett-Wilt, Mary E Rabaglia, Mark P Keller, Alan D Attie, Federico E Rey, John M Denu
Histone-modifying enzymes regulate transcription and are sensitive to availability of endogenous small-molecule metabolites, allowing chromatin to respond to changes in environment. The gut microbiota produces a myriad of metabolites that affect host physiology and susceptibility to disease; however, the underlying molecular events remain largely unknown. Here we demonstrate that microbial colonization regulates global histone acetylation and methylation in multiple host tissues in a diet-dependent manner: consumption of a "Western-type" diet prevents many of the microbiota-dependent chromatin changes that occur in a polysaccharide-rich diet...
December 1, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27887656/looking-beyond-the-cancer-cell-for-effective-drug-combinations
#6
Jonathan R Dry, Mi Yang, Julio Saez-Rodriguez
Combinations of therapies are being actively pursued to expand therapeutic options and deal with cancer's pervasive resistance to treatment. Research efforts to discover effective combination treatments have focused on drugs targeting intracellular processes of the cancer cells and in particular on small molecules that target aberrant kinases. Accordingly, most of the computational methods used to study, predict, and develop drug combinations concentrate on these modes of action and signaling processes within the cancer cell...
November 25, 2016: Genome Medicine
https://www.readbyqxmd.com/read/27880907/tet3-mediated-dna-demethylation-contributes-to-the-direct-conversion-of-fibroblast-to-functional-neuron
#7
Juan Zhang, Shuangquan Chen, Dongming Zhang, Zixiao Shi, Hong Li, Tongbiao Zhao, Baoyang Hu, Qi Zhou, Jianwei Jiao
The direct conversion of somatic cells to neurons by bypassing the multipotent cell state may be a powerful approach for personalized medicine. In addition to neuronal transcription factors and multiple small molecules, we find that epigenetic modification also contributes to the direct conversion of fibroblasts to neurons. Here, we show that Tet3, a DNA dioxygenase, can rapidly and efficiently convert fibroblasts directly into functional neurons. The induced neurons (iNs) express pan and mature neuronal markers such as Tuj1, Synapsin, and neuronal nuclei (NeuN)...
November 22, 2016: Cell Reports
https://www.readbyqxmd.com/read/27879268/transcriptional-selectivity-of-epigenetic-therapy-in-cancer
#8
Takahiro Sato, Matteo Cesaroni, Woonbok Chung, Shoghag Panjarian, Anthony Tran, Jozef Madzo, Yasuyuki Okamoto, Hanghang Zhang, Xiaowei Chen, Jaroslav Jelinek, Jean-Pierre J Issa
A central challenge in the development of epigenetic cancer therapy is the ability to direct selectivity in modulating gene expression for disease-selective efficacy. To address this issue, we characterized by RNA-seq, DNA methylation and ChIP-seq analyses the epigenetic response of a set of colon, breast and leukemia cancer cell lines to small molecule inhibitors against DNA methyltransferases (DAC), histone deacetylases (Depsi), histone demethylases (KDM1A inhibitor S2101), and histone methylases (EHMT2 inhibitor UNC0638 and EZH2 inhibitor GSK343)...
November 22, 2016: Cancer Research
https://www.readbyqxmd.com/read/27864925/drug-induced-pyoderma-gangrenosum-a-model-to-understand-the-pathogenesis-of-pyoderma-gangrenosum
#9
REVIEW
B C Wu, E D Patel, A G Ortega-Loayza
Pyoderma gangrenosum (PG) is a rare auto-inflammatory condition in which the alteration of neutrophil function and the innate immune response play key roles in its pathogenesis. Cases of PG have been reported in patients being treated with certain medications, which may help us to understand some of the possible pathways involved in the etiology of PG. The aim of this review is to review the cases of PG triggered by certain drugs and try to thoroughly understand the pathogenesis of the disease. To accomplish this, a PubMed search was completed using the following words: pyoderma gangrenosum, neutrophilic dermatosis, pathophysiology, drug-induced pyoderma gangrenosum...
November 19, 2016: British Journal of Dermatology
https://www.readbyqxmd.com/read/27848897/bioinformatics-and-drug-discovery
#10
Xuhua Xia
Bioinformatic analysis can not only accelerate drug target identification and drug candidate screening and refinement, but also facilitate characterization of side effects and predict drug resistance. High-throughput data such as genomic, epigenetic, genome architecture, cistromic, transcriptomic, proteomic, and ribosome profiling data have all made significant contribution to mechanism-based drug discovery and drug repurposing. Accumulation of protein and RNA structures, as well as development of homology modeling and protein structure simulation, coupled with large structure databases of small molecules and metabolites, paved the way for more realistic protein-ligand docking experiments and more informative virtual screening...
November 16, 2016: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/27834829/mirnas-and-mirna-polymorphisms-modify-drug-response
#11
REVIEW
Mu-Peng Li, Yao-Dong Hu, Xiao-Lei Hu, Yan-Jiao Zhang, Yong-Long Yang, Chun Jiang, Jie Tang, Xiao-Ping Chen
Differences in expression of drug response-related genes contribute to inter-individual variation in drugs' biological effects. MicroRNAs (miRNAs) are small noncoding RNAs emerging as new players in epigenetic regulation of gene expression at post-transcriptional level. MiRNAs regulate the expression of genes involved in drug metabolism, drug transportation, drug targets and downstream signal molecules directly or indirectly. MiRNA polymorphisms, the genetic variations affecting miRNA expression and/or miRNA-mRNA interaction, provide a new insight into the understanding of inter-individual difference in drug response...
November 8, 2016: International Journal of Environmental Research and Public Health
https://www.readbyqxmd.com/read/27834347/a-new-target-for-differentiation-therapy-in-aml
#12
Peilin Ma, Weihua Song, Jay L Hess
Despite major advances in understanding the genetics and epigenetics of acute myelogenous leukemia, there is still a great need to develop more specific and effective therapies. High throughput approaches involving either genetic approaches or small molecule inhibitor screens are beginning to identify promising new therapeutic targets.
November 11, 2016: Cell Research
https://www.readbyqxmd.com/read/27829312/cudc-907-promotes-bone-marrow-adipocytic-differentiation-through-inhibition-of-histone-deacetylase-and-regulation-of-cell-cycle
#13
Dalia Ali, Hassan Alshammari, Radhakrishnan Vishnubalaji, Elna Paul Chalisserry, Rimi Hamam, Musaed Alfayez, Moustapha Kassem, Abdullah Aldahmash, Nehad M Alajez
The role of bone marrow adipocytes (BMA) in overall energy metabolism and their effects on bone mass is currently an area of intensive investigation. BMA differentiate from bone marrow stromal cells (BMSCs), however, the molecular mechanisms regulating BMA differentiation are not fully understood. Herein, we investigated the effect of CUDC-907, identified by screening an epigenetics small-molecule library, on adipocytic differentiation of human BMSCs, and determined its molecular mechanism of action. hMSCs exposed to CUDC-907 (500 nM) exhibited enhanced adipocytic differentiation (~2...
November 9, 2016: Stem Cells and Development
https://www.readbyqxmd.com/read/27827996/the-bromodomain-and-extra-terminal-domain-bet-family-functional-anatomy-of-bet-paralogous-proteins
#14
REVIEW
Yasushi Taniguchi
The Bromodomain and Extra-Terminal Domain (BET) family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. The mammalian BET family of proteins comprises BRD2, BRD3, BRD4, and BRDT, which are encoded by paralogous genes that may have been generated by repeated duplication of an ancestral gene during evolution. Bromodomains that can specifically bind acetylated lysine residues in histones serve as chromatin-targeting modules that decipher the histone acetylation code...
November 7, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27827316/brm-promoter-polymorphisms-risk-and-survival-of-advanced-non-small-cell-lung-cancer-patients-in-the-princess-margaret-cohort-and-ncic-ctg-br-24-trial
#15
Geoffrey Liu, Sinead Cuffe, Shermi Liang, Abul K Azad, Lu Cheng, Yonathan Brhane, Xin Qiu, David W Cescon, Jeff P Bruce, Zhuo Chen, Dangxiao Cheng, Devalben Patel, Brandon C Tse, Scott A Laurie, Glenwood D Goss, Natasha B Leighl, Rayjean J Hung, Penelope A Bradbury, Lesley Seymour, Frances A Shepherd, Ming-Sound Tsao, Bingshu E Chen, Wei Xu, David Reisman
PURPOSE: BRM, a key catalytic subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene that is silenced in 15% of non-small cell lung cancer (NSCLC). Two novel BRM promoter polymorphisms (BRM-741, BRM-1321) are associated with reversible epigenetic silencing of BRM protein expression. EXPERIMENTAL DESIGN: Advanced NSCLC patients from the Princess Margaret (PM) cohort study and from the CCTG BR.24 clinical trial were genotyped for BRM promoter polymorphisms...
November 8, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27814427/cation-%C3%AF-interactions-in-crebbp-bromodomain-inhibition-an-electrostatic-model-for-small-molecule-binding-affinity-and-selectivity
#16
Wilian A Cortopassi, Kiran Kumar, Robert S Paton
CREBBP bromodomains, epigenetic "reader" proteins that recognize acetylated histone lysine residues, are a current target for cancer therapy. We show that experimental CREBBP binding affinities of small-molecules with aromatic or heteroaromatic functional groups are strongly influenced by a cation-π interaction with a positively charged arginine residue. For a series of fifteen 5-isoxazolylbenzimidazole derivatives, the strength of this non-covalent interaction is directly related to improvements in binding to CREBBP...
November 4, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27803105/bet-inhibitors-suppress-aldh-activity-by-targeting-aldh1a1-super-enhancer-in-ovarian-cancer
#17
Yuhki Yokoyama, Hengrui Zhu, Jeong Heon Lee, Andrew V Kossenkov, Sherry Y Wu, Jayamanna M Wickramasinghe, Xiangfan Yin, Katherine C Palozola, Alessandro Gardini, Louise C Showe, Kenneth S Zaret, Qin Liu, David Speicher, Jose R Conejo-Garcia, James E Bradner, Zhiguo Zhang, Anil K Sood, Tamas Ordog, Benjamin G Bitler, Rugang Zhang
The emergence of tumor cells with certain stem-like characteristics, such as high aldehyde dehydrogenase (ALDH) activity due to ALDH1A1 expression, contributes to chemotherapy resistance and tumor relapse. However, clinically applicable inhibitors of ALDH activity have not been reported. There is evidence to suggest that epigenetic regulation of stem-related genes contributes to chemotherapy efficacy. Here, we show that bromodomain and extraterminal (BET) inhibitors suppress ALDH activity by abrogating BRD4-mediated ALDH1A1 expression through a super-enhancer element and its associated enhancer RNA...
November 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27799566/epigenetic-gene-regulation-by-janus-kinase-1-in-diffuse-large-b-cell-lymphoma
#18
Lixin Rui, Amanda C Drennan, Michele Ceribelli, Fen Zhu, George W Wright, Da Wei Huang, Wenming Xiao, Yangguang Li, Kreg M Grindle, Li Lu, Daniel J Hodson, Arthur L Shaffer, Hong Zhao, Weihong Xu, Yandan Yang, Louis M Staudt
Janus kinases (JAKs) classically signal by activating STAT transcription factors but can also regulate gene expression by epigenetically phosphorylating histone H3 on tyrosine 41 (H3Y41-P). In diffuse large B-cell lymphomas (DLBCLs), JAK signaling is a feature of the activated B-cell (ABC) subtype and is triggered by autocrine production of IL-6 and IL-10. Whether this signaling involves STAT activation, epigenetic modification of chromatin, or both mechanisms is unknown. Here we use genetic and pharmacological inhibition to show that JAK1 signaling sustains the survival of ABC DLBCL cells...
October 31, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27785481/selected-small-molecules-as-inducers-of-pluripotency
#19
Małgorzata Baranek, Wojciech Markiewicz, Jan Barciszewski
The general idea of regenerative medicine is to fix or replace tissues or organs with live and patient-specific implants. Pluripotent stem cells are capable of indefinite self-renewal and differentiation into all cell types of the body. An easily accessible source of induced pluripotent stem cells (iPSCs) may allow obtaining and culturing tissues in vitro. Many approaches in the methods leading to obtain iPSCs have been tested in order to limit immunogenicity and tumorigenesis, and to increase efficiency. One of the approaches causing pluripotency is usage of small molecule compounds...
October 26, 2016: Acta Biochimica Polonica
https://www.readbyqxmd.com/read/27770356/localization-of-mirnas-by-in-situ-hybridization-in-plants-using-conventional-oligonucleotide-probes
#20
Sara Hernández-Castellano, Geovanny I Nic-Can, Clelia De-la-Peña
Among the epigenetic mechanisms studied with a greater interest in the last decade are the microRNAs (miRNAs). These small noncoding RNA sequences that are approximately 17-22 nucleotides in length play an essential role in many biological processes of various organisms, including plants. The analysis of spatiotemporal expression of miRNAs provides a better understanding of the role of these small molecules in plant development, cell differentiation, and other processes; but such analysis is also an important method for the validation of biological functions...
2017: Methods in Molecular Biology
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