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Small molecule epigenetics

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https://www.readbyqxmd.com/read/28630300/g9a-drives-hypoxia-mediated-gene-repression-for-breast-cancer-cell-survival-and-tumorigenesis
#1
Francesco Casciello, Fares Al-Ejeh, Greg Kelly, Donal J Brennan, Shin Foong Ngiow, Arabella Young, Thomas Stoll, Karolina Windloch, Michelle M Hill, Mark J Smyth, Frank Gannon, Jason S Lee
G9a is an epigenetic regulator that methylates H3K9, generally causing repression of gene expression, and participates in diverse cellular functions. G9a is genetically deregulated in a variety of tumor types and can silence tumor suppressor genes and, therefore, is important for carcinogenesis. Although hypoxia is recognized to be an adverse factor in tumor growth and metastasis, the role of G9a in regulating gene expression in hypoxia has not been described extensively. Here, we show that G9a protein stability is increased in hypoxia via reduced proline hydroxylation and, hence, inefficient degradation by the proteasome...
June 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28625826/drug-discovery-and-therapeutic-delivery-for-the-treatment-of-b-and-t-cell-tumors
#2
Regan Stephenson, Ankur Singh
Hematological malignancies manifest as lymphoma, leukemia, and myeloma, and remain a burden on society. From initial therapy to endless relapse-related treatment, societal burden is felt not only in the context of healthcare cost, but also in the compromised quality of life of patients. Long-term therapeutic strategies have become the standard in keeping hematological malignancies at bay as these cancers develop resistance to each round of therapy with time. As a result, there is a continual need for the development of new drugs to combat resistant disease in order to prolong patient life, if not to produce a cure...
June 15, 2017: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/28624514/bromodomain-containing-proteins-in-prostate-cancer
#3
REVIEW
Alfonso Urbanucci, Ian G Mills
Several oncogenic factors have been involved in prostate cancer progression. However, therapeutic approaches still focus on suppression of androgen receptor (AR) signaling. In fact, whereas the full-length AR incorporates a ligand-binding domain, which has become a drug target for competitive inhibitors, other transcription factors often do not have tractable binding pockets that aid drug development. Consequently drug development efforts have turned to transcription co-regulators, often chromatin-modifying enzymes or factors that bind to epigenetic modifications to chromatin...
June 14, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28607484/rare-cell-variability-and-drug-induced-reprogramming-as-a-mode-of-cancer-drug-resistance
#4
Sydney M Shaffer, Margaret C Dunagin, Stefan R Torborg, Eduardo A Torre, Benjamin Emert, Clemens Krepler, Marilda Beqiri, Katrin Sproesser, Patricia A Brafford, Min Xiao, Elliott Eggan, Ioannis N Anastopoulos, Cesar A Vargas-Garcia, Abhyudai Singh, Katherine L Nathanson, Meenhard Herlyn, Arjun Raj
Therapies that target signalling molecules that are mutated in cancers can often have substantial short-term effects, but the emergence of resistant cancer cells is a major barrier to full cures. Resistance can result from secondary mutations, but in other cases there is no clear genetic cause, raising the possibility of non-genetic rare cell variability. Here we show that human melanoma cells can display profound transcriptional variability at the single-cell level that predicts which cells will ultimately resist drug treatment...
June 15, 2017: Nature
https://www.readbyqxmd.com/read/28606761/inhibition-of-bromodomain-containing-protein-9-for-the-prevention-of-epigenetically-defined-drug-resistance
#5
Terry D Crawford, Steffan Vartanian, Alexandre Côté, Steve Bellon, Martin Duplessis, E Megan Flynn, Michael Hewitt, Hon-Ren Huang, James R Kiefer, Jeremy Murray, Christopher G Nasveschuk, Eneida Pardo, F Anthony Romero, Peter Sandy, Yong Tang, Alexander M Taylor, Vickie Tsui, Jian Wang, Shumei Wang, Laura Zawadzke, Brian K Albrecht, Steven R Magnuson, Andrea G Cochran, David Stokoe
Bromodomain-containing protein 9 (BRD9), an epigenetic "reader" of acetylated lysines on post-translationally modified histone proteins, is upregulated in multiple cancer cell lines. To assess the functional role of BRD9 in cancer cell lines, we identified a small-molecule inhibitor of the BRD9 bromodomain. Starting from a pyrrolopyridone lead, we used structure-based drug design to identify a potent and highly selective in vitro tool compound 11, (GNE-375). While this compound showed minimal effects in cell viability or gene expression assays, it showed remarkable potency in preventing the emergence of a drug tolerant population in EGFR mutant PC9 cells treated with EGFR inhibitors...
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28589491/synthesis-and-characterization-of-novel-bmi1-inhibitors-targeting-cellular-self-renewal-in-hepatocellular-carcinoma
#6
Monica Bartucci, Mohamed S Hussein, Eric Huselid, Kathleen Flaherty, Michele Patrizii, Saurabh V Laddha, Cindy Kui, Rachel A Bigos, John A Gilleran, Mervat M S El Ansary, Mona A M Awad, S David Kimball, David J Augeri, Hatem E Sabaawy
BACKGROUND: Hepatocellular carcinoma (HCC) represents one of the most lethal cancers worldwide due to therapy resistance and disease recurrence. Tumor relapse following treatment could be driven by the persistence of liver cancer stem-like cells (CSCs). The protein BMI1 is a member of the polycomb epigenetic factors governing cellular self-renewal, proliferation, and stemness maintenance. BMI1 expression also correlates with poor patient survival in various cancer types. OBJECTIVE: We aimed to elucidate the extent to which BMI1 can be used as a potential therapeutic target for CSC eradication in HCC...
June 6, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28573530/mecp2-regulates-ptch1-expression-through-dna-methylation-in-rheumatoid-arthritis
#7
Zheng-Hao Sun, Yan-Hui Liu, Jun-da Liu, Dan-Dan Xu, Xiao-Feng Li, Xiao-Ming Meng, Tao-Tao Ma, Cheng Huang, Jun Li
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, in which pathogenesis is not clear. Many research demonstrated that fibroblast-like synoviocytes (FLSs) play a key role in RA pathogenesis, join in the cartilage injury and hyperplasia of the synovium, and contribute to the release of inflammatory cytokines. We used adjuvant arthritis (AA) rats as RA animal models. The methyl-CpG-binding protein 2 (MeCP2) enables the suppressed chromatin structure to be selectively detected in AA FLSs. Overexpression of this protein leads to an increase of integral methylation levels...
June 1, 2017: Inflammation
https://www.readbyqxmd.com/read/28570543/a-simple-method-to-identify-kinases-that-regulate-embryonic-stem-cell-pluripotency-by-high-throughput-inhibitor-screening
#8
Charles A C Williams, Nathanael S Gray, Greg M Findlay
Embryonic stem cells (ESCs) can self-renew or differentiate into all cell types, a phenomenon known as pluripotency. Distinct pluripotent states have been described, termed "naïve" and "primed" pluripotency. The mechanisms that control naïve-primed transition are poorly understood. In particular, we remain poorly informed about protein kinases that specify naïve and primed pluripotent states, despite increasing availability of high-quality tool compounds to probe kinase function. Here, we describe a scalable platform to perform targeted small molecule screens for kinase regulators of the naïve-primed pluripotent transition in mouse ESCs...
May 12, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28564537/attach-pull-release-calculations-of-ligand-binding-and-conformational-changes-on-the-first-brd4-bromodomain
#9
Germano Heinzelmann, Niel M Henriksen, Michael K Gilson
Bromodomains, protein domains involved in epigenetic regulation, are able to bind small molecules with high affinity. In the present study, we report free energy calculations for the binding of seven ligands to the first BRD4 bromodomain, using the attach-pull-release (APR) method to compute the reversible work of removing the ligands from the binding site and then allowing the protein to relax conformationally. We test three different water models, TIP3P, TIP4PEw and SPC/E, as well as the GAFF and GAFF2 parameter sets for the ligands...
May 31, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28554227/modulating-epigenetic-memory-through-vitamins-and-tet-implications-for-regenerative-medicine-and-cancer-treatment
#10
Timothy A Hore
Vitamins A and C represent unrelated sets of small molecules that are essential to the human diet and have recently been shown to intensify erasure of epigenetic memory in naive embryonic stem cells. These effects are driven by complementary enhancement of the ten-eleven translocation (TET) demethylases - vitamin A stimulates TET expression, whereas vitamin C potentiates TET catalytic activity. Vitamin A and C cosupplementation synergistically enhances reprogramming of differentiated cells to the naive state, but overuse may exaggerate instability of imprinted genes...
June 2017: Epigenomics
https://www.readbyqxmd.com/read/28549975/knockdown-of-epigenetic-transcriptional-co-regulator-brd2a-disrupts-apoptosis-and-proper-formation-of-hindbrain-and-midbrain-hindbrain-boundary-mhb-region-in-zebrafish
#11
Tami Murphy, Heather Melville, Eliza Fradkin, Giana Bistany, Gregory Branigan, Kelly Olsen, Catharine R Comstock, Hayley Hanby, Ellie Garbade, Angela J DiBenedetto
Brd2 is a member of the bromodomain-extraterminal domain (BET) family of proteins and functions as an acetyl-histone-directed transcriptional co-regulator and recruitment scaffold in chromatin modification complexes affecting signal-dependent transcription. While Brd2 acts as a protooncogene in mammalian blood, developmental studies link it to regulation of neuronal apoptosis and epilepsy, and complete knockout of the gene is invariably embryonic lethal. In Drosophila, the Brd2 homolog acts as a maternal effect factor necessary for segment formation and identity and proper expression of homeotic loci, including Ultrabithorax and engrailed...
May 23, 2017: Mechanisms of Development
https://www.readbyqxmd.com/read/28548080/discovery-of-first-in-class-reversible-dual-small-molecule-inhibitors-against-g9a-and-dnmts-in-hematological-malignancies
#12
Edurne San José-Enériz, Xabier Agirre, Obdulia Rabal, Amaia Vilas-Zornoza, Juan A Sanchez-Arias, Estibaliz Miranda, Ana Ugarte, Sergio Roa, Bruno Paiva, Ander Estella-Hermoso de Mendoza, Rosa María Alvarez, Noelia Casares, Victor Segura, José I Martín-Subero, François-Xavier Ogi, Pierre Soule, Clara M Santiveri, Ramón Campos-Olivas, Giancarlo Castellano, Maite Garcia Fernandez de Barrena, Juan Roberto Rodriguez-Madoz, Maria José García-Barchino, Juan Jose Lasarte, Matias A Avila, Jose Angel Martinez-Climent, Julen Oyarzabal, Felipe Prosper
The indisputable role of epigenetics in cancer and the fact that epigenetic alterations can be reversed have favoured development of epigenetic drugs. In this study, we design and synthesize potent novel, selective and reversible chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity. In vitro treatment of haematological neoplasia (acute myeloid leukaemia-AML, acute lymphoblastic leukaemia-ALL and diffuse large B-cell lymphoma-DLBCL) with the lead compound CM-272, inhibits cell proliferation and promotes apoptosis, inducing interferon-stimulated genes and immunogenic cell death...
May 26, 2017: Nature Communications
https://www.readbyqxmd.com/read/28531195/livestock-metabolomics-and-the-livestock-metabolome-a-systematic-review
#13
Seyed Ali Goldansaz, An Chi Guo, Tanvir Sajed, Michael A Steele, Graham S Plastow, David S Wishart
Metabolomics uses advanced analytical chemistry techniques to comprehensively measure large numbers of small molecule metabolites in cells, tissues and biofluids. The ability to rapidly detect and quantify hundreds or even thousands of metabolites within a single sample is helping scientists paint a far more complete picture of system-wide metabolism and biology. Metabolomics is also allowing researchers to focus on measuring the end-products of complex, hard-to-decipher genetic, epigenetic and environmental interactions...
2017: PloS One
https://www.readbyqxmd.com/read/28530797/unexpected-biotransformation-of-the-hdac-inhibitor-vorinostat-yields-aniline-containing-fungal-metabolites
#14
Donovon A Adpressa, Kayla J Stalheim, Philip Jerome Proteau, Sandra Loesgen
The diversity of genetically encoded small molecules produced by filamentous fungi remains largely unexplored, which makes these fungi an attractive source for the discovery of new compounds. However, accessing their full chemical repertoire under common laboratory culture conditions is a challenge. Epigenetic manipulation of gene expression has become a well-established tool for overcoming this obstacle. Here we report that perturbation of the endophytic ascomycete Chalara sp. 6661, producer of the isofusidienol class of antibiotics, with the HDAC inhibitor vorinostat resulted in the production of four new modified xanthones...
May 22, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28529527/skeletal-muscle-cell-induction-from-pluripotent-stem-cells
#15
REVIEW
Yusaku Kodaka, Gemachu Rabu, Atsushi Asakura
Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the potential to differentiate into various types of cells including skeletal muscle cells. The approach of converting ESCs/iPSCs into skeletal muscle cells offers hope for patients afflicted with the skeletal muscle diseases such as the Duchenne muscular dystrophy (DMD). Patient-derived iPSCs are an especially ideal cell source to obtain an unlimited number of myogenic cells that escape immune rejection after engraftment. Currently, there are several approaches to induce differentiation of ESCs and iPSCs to skeletal muscle...
2017: Stem Cells International
https://www.readbyqxmd.com/read/28526414/a-novel-sirt1-inhibitor-4bb-induces-apoptosis-in-hct116-human-colon-carcinoma-cells-partially-by-activating-p53
#16
Ananga Ghosh, Amrita Sengupta, Guru Pavan Kumar Seerapu, Ali Nakhi, E V Venkat Shivaji Ramarao, Navneet Bung, Gopalakrishnan Bulusu, Manojit Pal, Devyani Haldar
The NAD+-dependent protein deacetylase SIRT1 has emerged as an important target for epigenetic therapeutics of colon cancer as its increased expression is associated with cancer progression. Additionally, SIRT1 represses p53 function via deacetylation, promoting tumor growth. Therefore, inhibition of SIRT1 is of great therapeutic interest for the treatment of colon cancer. Here, we report discovery of a novel quinoxaline based small molecule inhibitor of human SIRT1, 4bb, investigated its effect on viability of colon cancer cells and molecular mechanism of action...
May 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28516429/cardinal-epigenetic-role-of-non-coding-regulatory-rnas-in-circadian-rhythm
#17
REVIEW
Utpal Bhadra, Pradipta Patra, Manika Pal-Bhadra
Circadian rhythm which governs basic physiological activities like sleeping, feeding and energy consumption is regulated by light-controlled central clock genes in the pacemaker neuron. The timekeeping machinery with unique transcriptional and post-transcriptional feedback loops is controlled by different small regulatory RNAs in the brain. Roles of the multiple neuronal genes, especially post-transcriptional regulation, splicing, polyadenylation, mature mRNA editing, and stability of translation products, are controlled by epigenetic activities orchestrated via small RNAs...
May 17, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28507324/a-novel-indole-compound-ma-35-attenuates-renal-fibrosis-by-inhibiting-both-tnf-%C3%AE-and-tgf-%C3%AE-1-pathways
#18
Hisato Shima, Kensuke Sasaki, Takehiro Suzuki, Chikahisa Mukawa, Ten Obara, Yuki Oba, Akihiro Matsuo, Takayasu Kobayashi, Eikan Mishima, Shun Watanabe, Yasutoshi Akiyama, Koichi Kikuchi, Tetsuro Matsuhashi, Yoshitsugu Oikawa, Fumika Nanto, Yukako Akiyama, Hsin-Jung Ho, Chitose Suzuki, Daisuke Saigusa, Atsushi Masamune, Yoshihisa Tomioka, Takao Masaki, Sadayoshi Ito, Ken-Ichiro Hayashi, Takaaki Abe
Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) play key roles in progression of renal fibrosis, dual blockade of TGF-β1 and TNF-α is desired as its therapeutic approach. Here we screened small molecules showing anti-TNF-α activity in the compound library of indole derivatives. 11 out of 41 indole derivatives inhibited the TNF-α effect. Among them, Mitochonic Acid 35 (MA-35), 5-(3, 5-dimethoxybenzyloxy)-3-indoleacetic acid, showed the potent effect...
May 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28505447/interrogating-the-roles-of-post-translational-modifications-of-non-histone-proteins
#19
Zakey Yusuf Buuh, Zhigang Lyu, Rongsheng E Wang
Post-translational modifications (PTMs) allot versatility to the biological functions of highly conserved proteins. Recently, modifications to non-histone proteins such as methylation, acetylation, phosphorylation, glycosylation, ubiquitination, and many more have been linked to the regulation of pivotal pathways related to cellular response and stability. Due to the roles these dynamic modifications assume, their dysregulation has been associated with cancer and many other important diseases such as inflammatory disorders and neurodegenerative diseases...
May 15, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28504676/developing-spindlin1-small-molecule-inhibitors-by-using-protein-microarrays
#20
Narkhyun Bae, Monica Viviano, Xiaonan Su, Jie Lv, Donghang Cheng, Cari Sagum, Sabrina Castellano, Xue Bai, Claire Johnson, Mahmoud Ibrahim Khalil, Jianjun Shen, Kaifu Chen, Haitao Li, Gianluca Sbardella, Mark T Bedford
The discovery of inhibitors of methyl- and acetyl-binding domains has provided evidence for the 'druggability' of epigenetic effector molecules. The small-molecule probe UNC1215 prevents methyl-dependent protein-protein interactions by engaging the aromatic cage of MBT domains and, with lower affinity, Tudor domains. Using a library of tagged UNC1215 analogs, we screened a protein-domain microarray of human methyllysine effector molecules to rapidly detect compounds with new binding profiles with either increased or decreased specificity...
July 2017: Nature Chemical Biology
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