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Targetted small molecules

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https://www.readbyqxmd.com/read/29245156/selection-and-targeting-of-epcam-protein-by-ssdna-aptamer
#1
Walhan Alshaer, Nida Ababneh, Mamon Hatmal, Heba Izmirli, Moujab Choukeife, Alaa Shraim, Nour Sharar, Aya Abu-Shiekah, Fadwa Odeh, Abeer Al Bawab, Abdalla Awidi, Said Ismail
Aptamers are molecules that reveal highly complex and refined molecular recognition properties. These molecules are capable of binding with high affinity and selectivity to targets, ranging from small molecules to whole living cells. Several aptamers have been selected for targeting cellular proteins and they have also used in developing therapeutics and diagnostic strategies. Epithelial cell adhesion molecule (EpCAM) is considered as a cancer stem cell (CSC) biomarker and one of the most promising targets for aptamer selection against CSCs...
2017: PloS One
https://www.readbyqxmd.com/read/29243965/enasidenib-a-targeted-inhibitor-of-mutant-idh2-proteins-for-treatment-of-relapsed-or-refractory-acute-myeloid-leukemia
#2
Eytan M Stein
Mutations in IDH2 genes (mIDH2) occur in approximately 12% of patients with acute myeloid leukemia. Enasidenib is an oral, small-molecule inhibitor of mIDH2 proteins. Enasidenib is shown to suppress the oncometabolite, 2-hydroxyglutarate, and promote differentiation of leukemic bone marrow blasts. In a Phase I dose-escalation and expansion study, 40.3% of patients with relapsed/refractory acute myeloid leukemia responded to enasidenib monotherapy, including 19.3% who achieved complete remission and 11% who proceeded to transplant...
January 2018: Future Oncology
https://www.readbyqxmd.com/read/29243390/aquaporin-4-blockade-improves-survival-of-murine-heart-allografts-subjected-to-prolonged-cold-ischemia
#3
Katayoun Ayasoufi, Naoki Kohei, Michael Nicosia, Ran Fan, George W Farr, Paul R McGuirk, Marc F Pelletier, Robert L Fairchild, Anna Valujskikh
Prolonged cold ischemia storage (CIS) is a leading risk factor for poor transplant outcome. Existing strategies strive to minimize IRI in transplanted organs, yet there is a need for novel approaches to improve outcomes of marginal allografts and expand the pool of donor organs suitable for transplantation. Aquaporins (AQPs) are a family of water channels that facilitate homeostasis, tissue injury and inflammation. We tested whether inhibition of AQP4 improves the survival of fully MHC-mismatched murine cardiac allografts subjected to 8 h CIS...
December 15, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/29242642/targeting-mutant-p53-for-efficient-cancer-therapy
#4
REVIEW
Vladimir J N Bykov, Sofi E Eriksson, Julie Bianchi, Klas G Wiman
The tumour suppressor gene TP53 is the most frequently mutated gene in cancer. Wild-type p53 can suppress tumour development by multiple pathways. However, mutation of TP53 and the resultant inactivation of p53 allow evasion of tumour cell death and rapid tumour progression. The high frequency of TP53 mutation in tumours has prompted efforts to restore normal function of mutant p53 and thereby trigger tumour cell death and tumour elimination. Small molecules that can reactivate missense-mutant p53 protein have been identified by different strategies, and two compounds are being tested in clinical trials...
December 15, 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/29242512/synthetic-integrin-binding-immune-stimulators-target-cancer-cells-and-prevent-tumor-formation
#5
Manuel Brehs, André J G Pötgens, Julia Steitz, Karine Thewes, Janett Schwarz, Anne C Conibear, Matthias Bartneck, Frank Tacke, Christian F W Becker
Immuno-oncology approaches mainly utilize monoclonal antibodies or protein-based scaffolds that bind with high affinity to cancer cells and can generate an immune response. Peptides can also bind with high affinity to cancer cells and are intermediate in size between antibodies and small molecules. They are also synthetically accessible and therefore easily modified to optimize their stability, binding affinity and selectivity. Here we describe the design of immune system engagers (ISErs), a novel class of synthetic peptide-based compounds that bind specifically to cancer cells and stimulate the immune system...
December 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29241533/a-small-molecule-oligosaccharyltransferase-inhibitor-with-pan-flaviviral-activity
#6
Andreas S Puschnik, Caleb D Marceau, Yaw Shin Ooi, Karim Majzoub, Natalie Rinis, Joseph N Contessa, Jan E Carette
The mosquito-borne flaviviruses include important human pathogens such as dengue, Zika, West Nile, and yellow fever viruses, which pose a serious threat for global health. Recent genetic screens identified endoplasmic reticulum (ER)-membrane multiprotein complexes, including the oligosaccharyltransferase (OST) complex, as critical flavivirus host factors. Here, we show that a chemical modulator of the OST complex termed NGI-1 has promising antiviral activity against flavivirus infections. We demonstrate that NGI-1 blocks viral RNA replication and that antiviral activity does not depend on inhibition of the N-glycosylation function of the OST...
December 12, 2017: Cell Reports
https://www.readbyqxmd.com/read/29241453/bile-acid-is-a-significant-host-factor-shaping-the-gut-microbiome-of-diet-induced-obese-mice
#7
Xiaojiao Zheng, Fengjie Huang, Aihua Zhao, Sha Lei, Yunjing Zhang, Guoxiang Xie, Tianlu Chen, Chun Qu, Cynthia Rajani, Bing Dong, Defa Li, Wei Jia
BACKGROUND: Intestinal bacteria are known to regulate bile acid (BA) homeostasis via intestinal biotransformation of BAs and stimulation of the expression of fibroblast growth factor 19 through intestinal nuclear farnesoid X receptor (FXR). On the other hand, BAs directly regulate the gut microbiota with their strong antimicrobial activities. It remains unclear, however, how mammalian BAs cross-talk with gut microbiome and shape microbial composition in a dynamic and interactive way. RESULTS: We quantitatively profiled small molecule metabolites derived from host-microbial co-metabolism in mice, demonstrating that BAs were the most significant factor correlated with microbial alterations among all types of endogenous metabolites...
December 14, 2017: BMC Biology
https://www.readbyqxmd.com/read/29241295/in-vitro-selection-and-characterization-of-dna-aptamers-to-a-small-molecule-target
#8
Annamaria Ruscito, Erin M McConnell, Anna Koudrina, Ranganathan Velu, Christopher Mattice, Vernon Hunt, Maureen McKeague, Maria C DeRosa
Aptamers, synthetic oligonucleotide-based molecular recognition probes, have found use in a wide array of biosensing technologies based on their tight and highly selective binding to a variety of molecular targets. However, the inherent challenges associated with the selection and characterization of aptamers for small molecule targets have resulted in their underrepresentation, despite the need for small molecule detection in fields such as medicine, the environment, and agriculture. This protocol describes the steps in the selection, sequencing, affinity characterization, and truncation of DNA aptamers that are specific for small molecule targets...
December 14, 2017: Current Protocols in Chemical Biology
https://www.readbyqxmd.com/read/29241165/sc1-promotes-mir124-3p-expression-to-maintain-the-self-renewal-of-mouse-embryonic-stem-cells-by-inhibiting-the-mek-erk-pathway
#9
Qing Wei, Hongliang Liu, Zhiying Ai, Yongyan Wu, Yingxiang Liu, Zhaopeng Shi, Xuexue Ren, Zekun Guo
BACKGROUND/AIMS: Self-renewal is one of the most important features of embryonic stem (ES) cells. SC1 is a small molecule modulator that effectively maintains the self-renewal of mouse ES cells in the absence of leukemia inhibitory factor (LIF), serum and feeder cells. However, the mechanism by which SC1 maintains the undifferentiated state of mouse ES cells remains unclear. METHODS: In this study, microarray and small RNA deep-sequencing experiments were performed on mouse ES cells treated with or without SC1 to identify the key genes and microRNAs that contributed to self-renewal...
December 12, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29240857/the-latest-drugs-and-small-molecule-inhibitors-for-skin-and-hair
#10
Varun Kalhun, Neil Sadick
<p>Biologic drugs, a novel class of agents engineered to target specifc mediators of infammation, and small-molecule inhibitors that pen-etrate the cell membrane to interact with targets inside a cell represent the cutting-edge of pharmacological biomedical therapeutics. Clinical studies have already demonstrated the effectiveness of this new generation of drugs in treating a variety of medical illnesses and conditions that were refractory to traditional treatments. This review aims to describe the latest available or currently in-develop-ment drugs, biologic agents, and small molecule inhibitors for treatment of psoriasis, rosacea, alopecia areata, and atopic dermatitis...
December 1, 2017: Journal of Drugs in Dermatology: JDD
https://www.readbyqxmd.com/read/29240418/demonstrating-in-cell-target-engagement-using-a-pirin-protein-degradation-probe-cct367766
#11
Nicola E A Chessum, Swee Y Sharp, John J Caldwell, A Elisa Pasqua, Birgit Wilding, Giampiero Colombano, Ian Collins, Bugra Ozer, Meirion Richards, Martin G Rowlands, Mark Stubbs, Rosemary Burke, P Craig McAndrew, Paul A Clarke, Paul Workman, Matthew D Cheeseman, Keith Jones
Demonstrating intracellular protein target engagement is an essential step in the development and progression of new chemical probes and potential small molecule therapeutics. However, this can be particularly challenging for poorly studied and non-catalytic proteins, as robust proximal biomarkers are rarely known. To confirm that our recently discovered chemical probe 1 (CCT251236) binds the putative transcription factor regulator pirin in living cells, we developed a heterobifunctional protein degradation probe...
December 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29240402/structural-basis-of-aldh1a2-inhibition-by-irreversible-and-reversible-small-molecule-inhibitors
#12
Yan Chen, Jin-Yi Zhu, Kwon Ho Hong, David C Mikles, Gunda I Georg, Alex S Goldstein, John K Amory, Ernst Schönbrunn
The ALDH1A subfamily of aldehyde dehydrogenase enzymes are crucial in regulating retinoic acid (RA) signaling and have received attention as potential drug targets. ALDH1A2 is the primary RA-synthesizing enzyme in mammalian spermatogenesis and is therefore considered a viable drug target for male contraceptive development. However, only a small number of ALDH1A2 inhibitors have been reported, and information on the structure of ALDH1A2 was limited to the NAD-liganded enzyme void of substrate or inhibitors. Herein, we describe the mechanism of action of structurally unrelated reversible and irreversible inhibitors of human ALDH1A2 using direct binding studies and X-ray crystallography...
December 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29239327/influence-of-vascular-endothelial-growth-factor-and-radiation-on-gap-junctional-intercellular-communication-in-glioblastoma-multiforme-cell-lines
#13
Reinhardt Krcek, Pauline Latzer, Irenäus Anton Adamietz, Helmut Bühler, Carsten Theiss
Glioblastoma multiforme (GBM) is a highly aggressive glial brain tumor with an unfavorable prognosis despite all current therapies including surgery, radiation and chemotherapy. One characteristic of this tumor is a strong synthesis of vascular endothelial growth factor (VEGF), an angiogenesis factor, followed by pronounced vascularization. VEGF became a target in the treatment of GBM, for example with bevacizumab or the tyrosine kinase inhibitor axitinib, which blocks VEGF receptors. To improve patients' prognosis, new targets in the treatment of GBM are under investigations...
November 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/29239170/best-matched-internal-standard-normalization-in-liquid-chromatography-mass-spectrometry-metabolomics-applied-to-environmental-samples
#14
Angela K Boysen, Katherine Rose Heal, Laura Truxal Carlson, Anitra E Ingalls
The goal of metabolomics is to measure the entire range of small organic molecules in biological samples. In liquid chromatography-mass spectrometry-based metabolomics, formidable analytical challenges remain in removing the non-biological factors that affect chromatographic peak areas. These factors include sample matrix-induced ion suppression, chromatographic quality, and analytical drift. The combination of these factors is referred to as obscuring variation. Some metabolomics samples can exhibit intense obscuring variation due to matrix-induced ion suppression, rendering large amounts of data unreliable and difficult to interpret...
December 14, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/29237722/pannexin-1-channels-as-an-unexpected-new-target-of-the-anti-hypertensive-drug-spironolactone
#15
Miranda E Good, Yu-Hsin Chiu, Ivan K Poon, Christopher B Medina, Joshua T Butcher, Suresh K Mendu, Leon J DeLalio, Alexander W Lohman, Norbert Leitinger, Eugene J Barrett, Ulrike M Lorenz, Bimal N Desai, Iris Z Jaffe, Douglas Bayliss, Brant E Isakson, Kodi S Ravichandran
Rationale: Resistant hypertension is a major health concern with unknown etiology. Spironolactone is an effective anti-hypertensive drug, especially for patients with resistant hypertension, and is considered by the World Health Organization (WHO) as an "essential" medication. Although spironolactone can act at the mineralocorticoid receptor (NR3C2), there is increasing evidence of mineralocorticoid receptor (MR)-independent effects of spironolactone. Objective: Here, we detail the unexpected discovery that pannexin 1 (Panx1) channels could be a relevant in vivo target of spironolactone...
December 13, 2017: Circulation Research
https://www.readbyqxmd.com/read/29237428/nkx2-1-expression-as-a-prognostic-marker-in-early-stage-non-small-cell-lung-cancer
#16
Jorge Moisés, Alfons Navarro, Sandra Santasusagna, Nuria Viñolas, Laureano Molins, José Ramirez, Jeisson Osorio, Adela Saco, Joan Josep Castellano, Carmen Muñoz, Sara Morales, Mariano Monzó, Ramón María Marrades
BACKGROUND: NKX2-1, a key molecule in lung development, is highly expressed in non-small cell lung cancer (NSCLC), particularly in lung adenocarcinoma (ADK), where it is a diagnostic marker. Studies of the prognostic role of NKX2-1 in NSCLC have reported contradictory findings. Two microRNAs (miRNAs) have been associated with NKX2-1: miR-365, which targets NKX2-1; and miR-33a, which is downstream of NKX2-1. We have examined the effect of NKX2-1, miR-365 and miR-33a on survival in a cohort of early-stage NSCLC patients and in sub-groups of patients classified according to the mutational status of TP53, KRAS, and EGFR...
December 13, 2017: BMC Pulmonary Medicine
https://www.readbyqxmd.com/read/29237069/auxin-signaling-a-big-question-to-be-addressed-by-small-molecules
#17
Qian Ma, Peter Grones, Stéphanie Robert
Providing a mechanistic understanding of the crucial roles of the phytohormone auxin has been an important and coherent aspect of plant biology research. Since its discovery more than a century ago, prominent advances have been made in the understanding of auxin action, ranging from metabolism and transport to cellular and transcriptional responses. However, there is a long road ahead before a thorough understanding of its complex effects is achieved, because a lot of key information is still missing. The availability of an increasing number of technically advanced scientific tools has boosted the basic discoveries in auxin biology...
November 18, 2017: Journal of Experimental Botany
https://www.readbyqxmd.com/read/29236977/gene2drug-a-computational-tool-for-pathway-based-rational-drug-repositioning
#18
Francesco Napolitano, Diego Carrella, Barbara Mandriani, Sandra Pisonero, Francesco Sirci, Diego Medina, Nicola Brunetti-Pierri, Diego di Bernardo
Motivation: Drug repositioning has been proposed as an effective shortcut to drug discovery. The availability of large collections of transcriptional responses to drugs enables computational approaches to drug repositioning directly based on measured molecular effects. Results: We introduce a novel computational methodology for rational drug repositioning, which exploits the transcriptional responses following treatment with small molecule. Specifically, given a therapeutic target gene, a prioritisation of potential effective drugs is obtained by assessing their impact on the transcription of genes in the pathway(s) including the target...
December 11, 2017: Bioinformatics
https://www.readbyqxmd.com/read/29236775/active-site-targeted-covalent-irreversible-inhibitors-of-usp7-impair-the-functions-of-foxp3-t-regulatory-cells-by-promoting-ubiquitination-of-tip60
#19
Feng Wang, Liqing Wang, Jian Wu, Ivan Sokirniy, Phuong Nguyen, Thomas Bregnard, Joseph Weinstock, Michael Mattern, Irina Bezsonova, Wayne W Hancock, Suresh Kumar
Accumulation of Foxp3+ T-regulatory (Treg) cells in the tumor microenvironment is associated with tumor immune evasion and poor patient outcome in the case of many solid tumors. Current therapeutic strategies for blocking Treg functions are not Treg-specific, and display only modest and transient efficacy. Recent studies revealed that ubiquitin-specific protease 7 (USP7) is essential for Treg functions by stabilizing expression of Tip60 and Foxp3, which together are central to the development and maintenance of the Treg cell lineage...
2017: PloS One
https://www.readbyqxmd.com/read/29236465/g-quadruplex-induction-by-hairpin-pyrrole-imidazole-polyamide-dimer
#20
Shunsuke Obata, Sefan Asamitsu, Kaori Hashiya, Toshikazu Bando, Hiroshi Sugiyama
G-quadruplex (G4) is one type of higher-order structure of nucleic acids and is thought to play important roles in various biological events such as regulation of transcription and inhibition of DNA replication. Pyrrole-imidazole polyamides (PIPs) are programmable small molecules that can sequence-specifically bind with high affinity to the minor groove of double-stranded (ds) DNA. Herein, we designed head-to-head hairpin PIP dimers and their target dsDNA in a model G4-forming sequence. Using an electrophoresis mobility shift assay and transcription arrest assay, we found that PIP dimers could induce the structural change to G4 DNA from dsDNA through the recognition by one PIP dimer molecule of two duplex binding sites flanking both ends of the G4-forming sequence...
December 13, 2017: Biochemistry
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