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Targetted small molecules

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https://www.readbyqxmd.com/read/28650526/a-dual-administration-microtracer-technique-to-characterize-the-absorption-distribution-metabolism-and-excretion-of-14-c-seletalisib-ucb5857-in-healthy-subjects
#1
Eric Helmer, Jean-Marie Nicolas, Jeff Long, Ad F Roffel, Emma Jones, Hugues Chanteux, Nieves Diaz, Holly Garratt, Tjerk Bosje
Phosphoinositide 3 kinases are targets for development of small-molecule inhibitors to disrupt progression of immune-inflammatory diseases. This phase 1 open-label study (Eudract 2014-005353-39) evaluated the safety and relative bioavailability of 2 new seletalisib (UCB5857) formulations (A and B) compared with a reference formulation. Absolute bioavailability (period 1a, n = 6) and disposition and metabolism (period 1b, n = 6) of the reference formulation were evaluated: healthy subjects received 30 mg orally plus ∼20 μg of a (14) C-labeled microtracer (intravenously in 1a, orally in 1b)...
June 26, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28649853/cationic-liposome-co-encapsulation-of-smac-mimetic-and-zvad-using-a-novel-lipid-bilayer-fusion-loaded-with-mlkl-pdna-for-tumor-inhibition-in-vivo
#2
Dan Sun, Linshu Zhao, Junzhong Lin, Yun Zhao, Yu Zheng
The increase in multidrug resistance among colon cancer cells presents a challenge for the development of effective therapies. Small-molecule analogs of second mitochondria-derived activator of caspase (SMAC) mimetic in association with mixed lineage kinase domain-like protein (MLKL)-pDNA and z-VAD-fmk have shown ideal antitumor effects in colon cancer cells in vitro via induction of RIP3-dependent necroptosis. To achieve synergistic antitumor effects in vivo, liposomes loaded with SMAC mimetic, MLKL-pDNA and z-VAD-fmk have been developed using novel lipid fusion methods to co-localize the molecules of interest within the tumor cells...
June 26, 2017: Journal of Drug Targeting
https://www.readbyqxmd.com/read/28649104/-aging-and-homeostasis-development-of-novel-adipor-targeted-drugs-with-exercise-mimicking-and-anti-aging-properties
#3
Miki Okada-Iwabu, Toshimasa Yamauchi, Masato Iwabu, Takashi Kadowaki
We have so far clarified that adiponectin, an adipocyte-secreted physiologically active substance, is decreased with the onset of obesity and that lifestyle-related diseases are primarily accounted for by the systemically decreased action of adiponectin/adiponectin receptors(AdipoRs). The activation of adiponectin/AdipoR has caloric restrictive and exercise-mimicking effects thus prolonging lifespan. We were the first in the world to succeed in identifying small-molecule compounds that serve as seed compounds for candidate AdipoR-activating drugs...
2017: Clinical Calcium
https://www.readbyqxmd.com/read/28648527/targeting-the-thioredoxin-system-for-cancer-therapy
#4
REVIEW
Junmin Zhang, Xinming Li, Xiao Han, Ruijuan Liu, Jianguo Fang
Thioredoxin (Trx) and thioredoxin reductase (TrxR) are essential components of the Trx system which plays pivotal roles in regulating multiple cellular redox signaling pathways. In recent years TrxR/Trx have been increasingly recognized as an important modulator of tumor development, and hence targeting TrxR/Trx is a promising strategy for cancer treatment. In this review we first discuss the structural details of TrxR, the functions of the Trx system, and the rational of targeting TrxR/Trx for cancer treatment...
June 22, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28648526/applying-structure-based-drug-design-approaches-to-allosteric-modulators-of-gpcrs
#5
REVIEW
Miles Congreve, Christine Oswald, Fiona H Marshall
Structural insights have been revealed from X-ray co-complexes of a range of G protein-coupled receptors (GPCRs) and their allosteric ligands. The understanding of how small molecules can modulate the function of this important class of receptors by binding to a diverse range of pockets on and inside the proteins has had a profound impact on the structure-based drug design (SBDD) of new classes of therapeutic agents. The types of allosteric pockets and the mode of modulation as well as the advantages and disadvantages of targeting allosteric pockets (as opposed to the natural orthosteric site) are considered in the context of these new structural findings...
June 22, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28648461/the-structural-requirements-of-histone-deacetylase-inhibitors-saha-analogs-modified-at-the-c5-position-display-dual-hdac6-8-selectivity
#6
Ahmed T Negmeldin, Mary Kay H Pflum
Histone deacetylase (HDAC) proteins have emerged as important targets for anti-cancer drugs, with four small molecules approved for use in the clinic. Suberoylanilide hydroxamic acid (Vorinostat, SAHA) was the first FDA-approved HDAC inhibitor for cancer treatment. However, SAHA inhibits most of the eleven HDAC isoforms. To understand the structural requirements of HDAC inhibitor selectivity and develop isoform selective HDAC inhibitors, SAHA analogs modified in the linker at the C5 position were synthesized and tested for potency and selectivity...
June 13, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28648379/targeted-protein-degradation-from-chemical-biology-to-drug-discovery
#7
REVIEW
Philipp M Cromm, Craig M Crews
Traditional pharmaceutical drug discovery is almost exclusively focused on directly controlling protein activity to cure diseases. Modulators of protein activity, especially inhibitors, are developed and applied at high concentration to achieve maximal effects. Thereby, reduced bioavailability and off-target effects can hamper compound efficacy. Nucleic acid-based strategies that control protein function by affecting expression have emerged as an alternative. However, metabolic stability and broad bioavailability represent development hurdles that remain to be overcome for these approaches...
June 10, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28648376/sam68-allows-selective-targeting-of-human-cancer-stem-cells
#8
Yannick D Benoit, Ryan R Mitchell, Ruth M Risueño, Luca Orlando, Borko Tanasijevic, Allison L Boyd, Lili Aslostovar, Kyle R Salci, Zoya Shapovalova, Jennifer Russell, Masakatsu Eguchi, Diana Golubeva, Monica Graham, Anargyros Xenocostas, Michael R Trus, Ronan Foley, Brian Leber, Tony J Collins, Mickie Bhatia
Targeting of human cancer stem cells (CSCs) requires the identification of vulnerabilities unique to CSCs versus healthy resident stem cells (SCs). Unfortunately, dysregulated pathways that support transformed CSCs, such as Wnt/β-catenin signaling, are also critical regulators of healthy SCs. Using the ICG-001 and CWP family of small molecules, we reveal Sam68 as a previously unappreciated modulator of Wnt/β-catenin signaling within CSCs. Disruption of CBP-β-catenin interaction via ICG-001/CWP induces the formation of a Sam68-CBP complex in CSCs that alters Wnt signaling toward apoptosis and differentiation induction...
June 21, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28647672/therapeutic-targeting-of-nuclear-export-inhibition-in-lung-cancer
#9
Arjun Gupta, Jessica M Saltarski, Michael A White, Pier P Scaglioni, David E Gerber
Intracellular compartmentalization and trafficking of molecules plays a critical role in complex and essential cellular processes. In lung cancer and other malignancies, aberrant nucleocytoplasmic transport of tumor suppressor proteins and cell cycle regulators results in tumorigenesis and inactivation of apoptosis. Pharmacologic targeting of this process, termed selective inhibition of nuclear export (SINE), has demonstrated anti-tumor efficacy in preclinical models and human clinical trials. Exportin-1 (XPO1)-which serves as the sole exporter of several tumor suppressor proteins and cell cycle regulators, including retinoblastoma (Rb), adenomatous polyposis coli (APC), p53, p73, p21, p27, FOXO, STAT3, IKB, topoisomerase II and PAR-4-is the principal focus of SINE drug development...
June 21, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28647528/the-linkage-between-nutrient-supply-intracellular-enzyme-abundances-and-bacterial-growth-new-evidences-from-the-central-carbon-metabolism-of-corynebacterium-glutamicum
#10
Stephan Noack, Raphael Voges, Jochem Gätgens, Wolfgang Wiechert
Corynebacterium glutamicum serves as important production host for small molecular compounds that are derived from precursor molecules of the central carbon metabolism. It is therefore a well-studied model organism of industrial biotechnology. However, a deeper understanding of the regulatory principles underlying the synthesis of central metabolic enzymes under different environmental conditions as well as its impact on cell growth is still missing. We studied enzyme abundances in C. glutamicum in response to growth on: i) one limiting carbon source by sampling chemostat and fed-batch cultivations and ii) changing carbon sources provided in excess by sampling batch cultivations...
June 21, 2017: Journal of Biotechnology
https://www.readbyqxmd.com/read/28647392/a-novel-dual-inhibitor-of-microtubule-and-bruton-s-tyrosine-kinase-inhibits-survival-of-multiple-myeloma-and-osteoclastogenesis
#11
Manoj K Pandey, Krishne Gowda, Shen-Shu Sung, Thomas Abraham, Tulin Budak-Alpdogan, Giampolo Talamo, Sinisa Dovat, Shantu Amin
Bruton's tyrosine kinase (BTK) regulates many vital signaling pathways and play critical role in cell proliferation, survival, migration, and resistance. Earlier we reported that a small molecule KS99 is an inhibitor of tubulin polymerization. In the present study we explored that whether KS99 is a dual inhibitor of BTK and tubulin polymerization. While it is known that BTK is required for clonogenic growth, and resistance; and microtubules are essential for cancer cell growth; dual targeting of these two components has not been explored...
June 21, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28647087/the-evolution-of-library-design-crafting-smart-compound-collections-for-phenotypic-screens
#12
REVIEW
Kerry L Spear, Scott P Brown
The (re)emergence of phenotypic drug discovery has been marked by a growing interest in screening campaigns that utilize phenotypic assays. The key objectives of phenotypic screens are different from those of target-based screens and can require alternate library-design strategies. Designing a library that is appropriate to the selected assay increases the likelihood of identifying better quality hits, which can reduce both timelines and overall cost of the drug-discovery process. Here, we provide an overview of small-molecule library design principles as applied to phenotypic screening...
March 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/28646172/dacomitinib-a-pan-inhibitor-of-erbb-receptors-suppresses-growth-and-invasive-capacity-of-chemoresistant-ovarian-carcinoma-cells
#13
Majid Momeny, Ghazaleh Zarrinrad, Farima Moghaddaskho, Arash Poursheikhani, Ghazaleh Sankanian, Azam Zaghal, Shahab Mirshahvaladi, Fatemeh Esmaeili, Haniyeh Eyvani, Farinaz Barghi, Zahra Sabourinejad, Zivar Alishahi, Hassan Yousefi, Reza Ghasemi, Leila Dardaei, Davood Bashash, Bahram Chahardouli, Ahmad R Dehpour, Javad Tavakkoly-Bazzaz, Kamran Alimoghaddam, Ardeshir Ghavamzadeh, Seyed H Ghaffari
Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination of EOC cells are the major reasons for low survival rate. Targeting signal transduction pathways which promote therapy resistance and metastatic dissemination is the key to successful treatment. Members of the ErbB family of receptors are over-expressed in EOC and play key roles in chemoresistance and invasiveness. Despite this, single-targeted ErbB inhibitors have demonstrated limited activity in chemoresistant EOC...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28645739/mir-1224-inhibits-cell-proliferation-in-acute-liver-failure-by-targeting-the-antiapoptotic-gene-nfib
#14
Sanchari Roy, Heike Bantel, Franziska Wandrer, Anne Theres Schneider, Jeremie Gautheron, Mihael Vucur, Frank Tacke, Christian Trautwein, Tom Luedde, Christoph Roderburg
BACKGROUND AND AIMS: Patient outcome in acute liver failure (ALF) is crucially determined by the appropriate balance between cell death and compensatory cell proliferation. MicroRNAs (miRNAs) - small non-coding RNAs that function as guide molecules in RNA silencing - have evolved as crucial mediators of nearly all developmental and pathological processes including physiology and disease of the liver. We investigated the role of miR-1224 during ALF. METHODS: We measured miR-1224 in livers of mice in various acute liver disease murine models and in ALF patients using quantitative real-time polymerase chain reaction...
June 20, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28645563/bruceine-d-inhibits-hepatocellular-carcinoma-growth-by-targeting-%C3%AE-catenin-jagged1-pathways
#15
Ziying Cheng, Xing Yuan, Yi Qu, Xia Li, Guozhen Wu, Chenwei Li, Xianpeng Zu, Niao Yang, Xisong Ke, Juan Zhou, Ning Xie, Xike Xu, Shanrong Liu, Yunheng Shen, Huiliang Li, Weidong Zhang
Hepatocellular carcinoma (HCC) is known for high mortality and limited available treatments. Aberrant activation of the Wnt and Notch signaling pathways is critical to liver carcinogenesis and progression. Here, we identified a small molecule, bruceine D (BD), as a Notch inhibitor, using an RBP-Jκ-dependent luciferase-reporter system. BD significantly inhibited liver tumor growth and enhanced the therapeutic effects of sorafenib in various murine HCC models. Mechanistically, BD promotes proteasomal degradation of β-catenin and the depletion of its nuclear accumulation, which in turn disrupts the Wnt/β-catenin-dependent transcription of the Notch ligand Jagged1 in HCC...
June 20, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28645106/phorbol-esters-dppa-dpa-promote-furin-expression-involving-transcription-factor-cebp%C3%AE-in-neuronal-cells
#16
Jing-Si Zha, Bing-Lin Zhu, Lu Liu, Yu-Jie Lai, Yan Long, Xiao-Tong Hu, Xiao-Juan Deng, Xue-Feng Wang, Zhen Yan, Guo-Jun Chen
Using high-throughput small molecule screening targeting furin gene, we identified that phorbol esters dPPA (12-Deoxyphorbol 13-phenylacetate 20-acetate) and dPA (12-Deoxyphorbol 13-acetate) significantly increased furin protein and mRNA expression in SH-SY5Y cells. This effect was prevented by PKC (protein kinase C) inhibitor calphostin C but not Ro318220, suggesting that the C1 domain, rather than the catalytic domain of PKC plays an important role. Luciferase assay revealed that nucleotides -7925 to -7426 were sufficient to mediate dPPA/dPA enhancement of furin P1 promoter activity...
June 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28644482/one-thousand-fold-enhancement-of-high-field-liquid-nuclear-magnetic-resonance-signals-at-room-temperature
#17
Guoquan Liu, Marcel Levien, Niels Karschin, Giacomo Parigi, Claudio Luchinat, Marina Bennati
Nuclear magnetic resonance (NMR) is a fundamental spectroscopic technique for the study of biological systems and materials, molecular imaging and the analysis of small molecules. It detects interactions at very low energies and is thus non-invasive and applicable to a variety of targets, including animals and humans. However, one of its most severe limitations is its low sensitivity, which stems from the small interaction energies involved. Here, we report that dynamic nuclear polarization in liquid solution and at room temperature can enhance the NMR signal of (13)C nuclei by up to three orders of magnitude at magnetic fields of ∼3 T...
July 2017: Nature Chemistry
https://www.readbyqxmd.com/read/28644160/calcitonin-gene-related-peptide-targeted-therapies-for-migraine-and-cluster-headache-a-review
#18
Nathaniel M Schuster, Alan M Rapoport
Calcitonin gene-related peptide (CGRP) is a signaling neuropeptide released from activated trigeminal sensory afferents in headache and facial pain disorders. There are a handful of CGRP-targeted therapies currently in phase 3 studies for migraine acute treatment or prevention. Currently, 4 monoclonal antibodies targeting either the CGRP ligand or receptor are being studied for migraine prevention: ALD403 (eptinezumab), AMG 334 (erenumab), LY2951742 (galcanezumab), and TEV-48125 (fremanezumab). Meanwhile, 1 small-molecule CGRP receptor antagonist (ubrogepant, MK-1602) is currently in phase 3 studies for the acute treatment of migraine...
June 21, 2017: Clinical Neuropharmacology
https://www.readbyqxmd.com/read/28644007/cyclotides-as-tools-in-chemical-biology
#19
Simon J de Veer, Joachim Weidmann, David J Craik
Among the various molecules that plants produce for defense against pests and pathogens, cyclotides stand out as exceptionally stable and structurally unique. These ribosomally synthesized peptides are around 30 amino acids in size, and are stabilized by a head-to-tail cyclic peptide backbone and three disulfide bonds that form a cystine knot. They occur in certain plants of the Rubiaceae, Violaceae, Cucurbitaceae, Fabaceae, and Solanaceae families, with an individual plant producing up to hundreds of different cyclotides...
June 23, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28643924/exosomes-novel-regulators-of-bone-remodelling-and-potential-therapeutic-agents-for-orthodontics
#20
REVIEW
L S Holliday, K P McHugh, J Zuo, J I Aguirre, J K Neubert, W J Rody
Recent studies suggest that exosomes are involved in intercellular communication required for the maintenance of healthy bone. Exosomes are small (30-150 nm in diameter) extracellular vesicles that are formed in multivesicular bodies and are released from cells as the multivesicular bodies fuse with the plasma membrane. Regulatory exosomes have the capacity to exert profound control over target cells. They can stimulate plasma membrane receptors and are also internalized by the target cell delivering proteins, lipids, small molecules and functional RNAs from the cell of origin...
June 2017: Orthodontics & Craniofacial Research
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