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https://www.readbyqxmd.com/read/29045862/the-two-state-prehensile-tail-of-the-antibacterial-toxin-colicin-n
#1
Christopher L Johnson, Alexandra S Solovyova, Olli Hecht, Colin Macdonald, Helen Waller, J Günter Grossmann, Geoffrey R Moore, Jeremy H Lakey
Intrinsically disordered regions within proteins are critical elements in many biomolecular interactions and signaling pathways. Antibacterial toxins of the colicin family, which could provide new antibiotic functions against resistant bacteria, contain disordered N-terminal translocation domains (T-domains) that are essential for receptor binding and the penetration of the Escherichia coli outer membrane. Here we investigate the conformational behavior of the T-domain of colicin N (ColN-T) to understand why such domains are widespread in toxins that target Gram-negative bacteria...
October 17, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/29045389/molecular-basis-of-usp7-inhibition-by-selective-small-molecule-inhibitors
#2
Andrew P Turnbull, Stephanos Ioannidis, Wojciech W Krajewski, Adan Pinto-Fernandez, Claire Heride, Agnes C L Martin, Louise M Tonkin, Elizabeth C Townsend, Shane M Buker, David R Lancia, Justin A Caravella, Angela V Toms, Thomas M Charlton, Johanna Lahdenranta, Erik Wilker, Bruce C Follows, Nicola J Evans, Lucy Stead, Cristina Alli, Vladislav V Zarayskiy, Adam C Talbot, Alexandre J Buckmelter, Minghua Wang, Crystal L McKinnon, Fabienne Saab, Joanna F McGouran, Hannah Century, Malte Gersch, Marc S Pittman, C Gary Marshall, Tony M Raynham, Mary Simcox, Lorna M D Stewart, Sheila B McLoughlin, Jaime A Escobedo, Kenneth W Bair, Christopher J Dinsmore, Tim R Hammonds, Sunkyu Kim, Sylvie Urbé, Michael J Clague, Benedikt M Kessler, David Komander
Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells...
October 18, 2017: Nature
https://www.readbyqxmd.com/read/29045385/usp7-small-molecule-inhibitors-interfere-with-ubiquitin-binding
#3
Lorna Kategaya, Paola Di Lello, Lionel Rougé, Richard Pastor, Kevin R Clark, Jason Drummond, Tracy Kleinheinz, Eva Lin, John-Paul Upton, Sumit Prakash, Johanna Heideker, Mark McCleland, Maria Stella Ritorto, Dario R Alessi, Matthias Trost, Travis W Bainbridge, Michael C M Kwok, Taylur P Ma, Zachary Stiffler, Bradley Brasher, Yinyan Tang, Priyadarshini Jaishankar, Brian R Hearn, Adam R Renslo, Michelle R Arkin, Frederick Cohen, Kebing Yu, Frank Peale, Florian Gnad, Matthew T Chang, Christiaan Klijn, Elizabeth Blackwood, Scott E Martin, William F Forrest, James A Ernst, Chudi Ndubaku, Xiaojing Wang, Maureen H Beresini, Vickie Tsui, Carsten Schwerdtfeger, Robert A Blake, Jeremy Murray, Till Maurer, Ingrid E Wertz
The ubiquitin system regulates essential cellular processes in eukaryotes. Ubiquitin is ligated to substrate proteins as monomers or chains and the topology of ubiquitin modifications regulates substrate interactions with specific proteins. Thus ubiquitination directs a variety of substrate fates including proteasomal degradation. Deubiquitinase enzymes cleave ubiquitin from substrates and are implicated in disease; for example, ubiquitin-specific protease-7 (USP7) regulates stability of the p53 tumour suppressor and other proteins critical for tumour cell survival...
October 18, 2017: Nature
https://www.readbyqxmd.com/read/29045152/discovery-of-potent-and-orally-bioavailable-macrocyclic-peptide-peptoid-hybrid-cxcr7-modulators
#4
Markus Boehm, Kevin Beaumont, Rhys M Jones, Amit S Kalgutkar, Liying Zhang, Karen Atkinson, Guoyun Bai, Janice A Brown, Heather Eng, Gilles H Goetz, Brian R Holder, Bhagyashree Khunte, Sarah Lazzaro, Chris Limberakis, Sangwoo Ryu, Michael J Shapiro, Laurie Tylaska, Jiangli Yan, Rushia Turner, Siegfried S F Leung, Mahesh Ramaseshan, David A Price, Spiros Liras, Matthew P Jacobson, David J Earp, R Scott Lokey, Alan M Mathiowetz, Elnaz Menhaji-Klotz
The chemokine receptor CXCR7 is an attractive target for a variety of diseases. While several small molecule modulators of CXCR7 have been reported, peptidic macrocycles may provide advantages in terms of potency, selectivity, and reduced off-target activity. We produced a series of peptidic macrocycles that incorporate an N-linked peptoid functionality where the peptoid group enabled us to explore side chain diversity well beyond that of natural amino acids. At the same time, computational calculations and experimental assays were used to track and reduce polarity while closely monitoring physicochemical properties...
October 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29045015/the-small-molecule-mertk-inhibitor-unc2025-decreases-platelet-activation-and-prevents-thrombosis
#5
Brian R Branchford, Timothy J Stalker, Luke Law, Gilbert Acevedo, Susan Sather, Christine Brzezinski, Katina M Wilson, Katherine Minson, Alisa B Lee-Sherick, Pavel Davizon-Castillo, Christopher Ng, Weihe Zhang, Keith B Neeves, Steven R Lentz, Xiaodong Wang, Stephen V Frye, H Shelton Earp, Deborah DeRyckere, Lawrence F Brass, Douglas K Graham, Jorge A Di Paola
BACKGROUND: Gas6 signals through the TAM (TYRO-3, AXL, MERTK) receptor family mediating platelet activation and thrombus formation via activation of the aggregate-stabilizing αIIb β3 integrin. OBJECTIVE: Here we describe anti-thrombotic effects mediated by UNC2025, a small molecule MERTK tyrosine kinase inhibitor. METHODS: MERTK phosphorylation and downstream signaling were assessed by immunoblot. Light transmission aggregometry, flow cytometry, and microfluidic analysis were used to evaluate the impact of MERTK inhibition on platelet activation and stability of aggregate formation in vitro...
October 17, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29044784/mechanism-based-inhibitors-of-the-human-sirtuin-5-deacylase-structure-activity-relationship-biostructural-and-kinetic-insight
#6
Nima Rajabi, Marina Auth, Kathrin R Troelsen, Martin Pannek, Dhaval Bhatt, Martin Fontenas, Matthew D Hirshey, Clemens Steegborn, Andreas S Madsen, Christian Adam Olsen
The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co-crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more "drug-like" properties...
October 17, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/29044377/heparosan-coated-liposomes-for-drug-delivery
#7
Rachel S Lane, F Michael Haller, Anais A E Chavaroche, Andrew Almond, Paul L DeAngelis
Liposomal encapsulation is a useful drug delivery strategy for small molecules, especially chemotherapeutic agents such as doxorubicin. Doxil® is a doxorubicin-containing liposome ("dox-liposome") that passively targets drug to tumors while reducing side effects caused by free drug permeating and poisoning healthy tissues. Polyethylene glycol (PEG) is the hydrophilic coating of Doxil® that protects the formulation from triggering the mononuclear phagocyte system (MPS). Evading the MPS prolongs dox-liposome circulation time thus increasing drug deposition at the tumor site...
November 1, 2017: Glycobiology
https://www.readbyqxmd.com/read/29042798/crizotinib-a-met-inhibitor-inhibits-growth-migration-and-invasion-of-breast-cancer-cells-in-vitro-and-synergizes-with-chemotherapeutic-agents
#8
Nehad M Ayoub, Kamal M Al-Shami, Mohammad A Alqudah, Nizar M Mhaidat
MET is a receptor tyrosine kinase known for its pleiotropic effects in tumorigenesis. Dysregulations of MET expression and/or signaling have been reported and determined to be associated with inferior outcomes in breast cancer patients rendering MET a versatile candidate for targeted therapeutic intervention. Crizotinib is a multi-targeted small-molecule kinase inhibitor for MET, ALK, and ROS1 kinases. This study evaluated the anti-proliferative, cytotoxic, anti-migratory, and anti-invasive effects of crizotinib in breast cancer cells in vitro...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29042487/differential-response-of-glioma-stem-cells-to-arsenic-trioxide-therapy-is-regulated-by-mnk1-and-mrna-translation
#9
Jonathan B Bell, Frank Eckerdt, Harshil Dhruv, Darren Finlay, Sen Peng, Seungchan Kim, Barbara Kroczynska, Elspeth Beauchamp, Kristen Alley, Jessica Clymer, Stewart Goldman, Shi-Yuan Cheng, C David James, Ichiro Nakano, Craig Horbinski, Andrew P Mazar, Kristiina Vuori, Priya Kumthekar, Jeffery Raizer, Michael E Berens, Leonidas C Platanias
Mesenchymal (MES) and proneural (PN) are two distinct glioma stem cells (GSCs) populations that drive therapeutic resistance in glioblastoma (GBM). We screened a panel of 650 small molecules against patient-derived GBM cells to discover compounds targeting specific GBM subtypes. Arsenic trioxide (ATO), a FDA-approved drug that crosses the blood-brain barrier, was identified as a potent PN-specific compound in the initial screen and follow-up validation studies. Furthermore, MES and PN GSCs exhibited differential sensitivity to ATO...
October 17, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29041897/small-molecule-modulation-of-splicing-factor-expression-is-associated-with-rescue-from-cellular-senescence
#10
Eva Latorre, Vishal C Birar, Angela N Sheerin, J Charles C Jeynes, Amy Hooper, Helen R Dawe, David Melzer, Lynne S Cox, Richard G A Faragher, Elizabeth L Ostler, Lorna W Harries
BACKGROUND: Altered expression of mRNA splicing factors occurs with ageing in vivo and is thought to be an ageing mechanism. The accumulation of senescent cells also occurs in vivo with advancing age and causes much degenerative age-related pathology. However, the relationship between these two processes is opaque. Accordingly we developed a novel panel of small molecules based on resveratrol, previously suggested to alter mRNA splicing, to determine whether altered splicing factor expression had potential to influence features of replicative senescence...
October 17, 2017: BMC Cell Biology
https://www.readbyqxmd.com/read/29041842/identifying-novel-small-molecule-antagonists-for-mlst8-protein-using-computational-approaches
#11
Tuleshwori Devi Sapam, Anbumani Velmurugan Ilavarasi, Bhagath Kumar Palaka, Elakkiya Elumalai, Nirmala Devi Kanika, Dinakara Rao Ampasala
Mammalian lethal with SEC13 protein 8 (mLST8), is an indispensable protein subunit of mammalian target of rapamycin (mTOR) signaling pathway that interacts with the kinase domain of mTOR protein, thereby stabilizing its active site. Experimental studies reported the over expression of mLST8 in human colon and prostate cancers by activation of both mTORC1/2 complexes and subsequent downstream substrates leading to tumor progression. Considering its role, targeting mLST8 protein would be a therapeutic approach against tumor progression in colon and prostate cancers...
October 17, 2017: Journal of Receptor and Signal Transduction Research
https://www.readbyqxmd.com/read/29041476/segmented-detection-spr-sensor-based-on-seven-core-fiber
#12
Yong Wei, Yudong Su, Chunlan Liu, Yonghui Zhang, Xiangfei Nie, Zhihai Liu, Yu Zhang, Feng Peng
By using a seven-core fiber (SCF), we propose and demonstrate a novel segmented detection SPR sensor, which solves two bottlenecks about the fiber SPR sensor of low sensitivity and the difficulty in the multichannel detection. The proposed sensor has ultra high sensitivity and wide detection range because of employing the segmented detection technology. Besides that, the proposed sensor employs reflection-type time division multiplexing (TDM) technology in fiber multichannel detection for the first time. We couple light into and out of the six circularly symmetric distributed cores of the seven-core fiber to realize the three channel SPR sensing and testing...
September 4, 2017: Optics Express
https://www.readbyqxmd.com/read/29040675/fluctuation-localization-imaging-based-fluorescence-in-situ-hybridization-flifish-for-accurate-detection-and-counting-of-rna-copies-in-single-cells
#13
Yi Cui, Dehong Hu, Lye Meng Markillie, William B Chrisler, Matthew J Gaffrey, Charles Ansong, Lori Sussel, Galya Orr
Quantitative gene expression analysis in intact single cells can be achieved using single molecule-based fluorescence in situ hybridization (smFISH). This approach relies on fluorescence intensity to distinguish between true signals, emitted from an RNA copy hybridized with multiple oligonucleotide probes, and background noise. Thus, the precision in smFISH is often compromised by partial or nonspecific probe binding and tissue autofluorescence, especially when only a small number of probes can be fitted to the target transcript...
October 4, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29039579/co%C3%A2-expression-of-murine-double-minute-2-sirna-and-wild%C3%A2-type-p53-induces-g1-cell-cycle-arrest-in-h1299-cells
#14
Long Liu, Ping Zhang, Hua Guo, Xinyu Tang, Lianqin Liu, Jiuling Li, Rui Guo, Yangyang Cai, Yanan Liu, Yang Li
The therapeutic options available for the treatment of advanced non-small cell lung cancer have increased over the past decade. Small molecule gene therapy has emerged as an effective therapy for the treatment of lung cancer in vitro and in vivo although it has not been tested in a clinical setting. In particular, therapies that target the negative feedback loop between p53 and murine double minute 2 (MDM2) provide a favorable outcome by maintaining activation of the tumor suppressor gene p53. The present study used transfection to simultaneously knockdown MDM2 expression using small interfering (si)RNA, and overexpress wild‑type p53 in H1299 cells...
October 11, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29039474/evaluation-of-a-radiocobalt-labelled-affibody-molecule-for-imaging-of-human-epidermal-growth-factor-receptor-3-expression
#15
Maria Rosestedt, Ken G Andersson, Bogdan Mitran, Sara S Rinne, Vladimir Tolmachev, John Löfblom, Anna Orlova, Stefan Ståhl
The human epidermal growth factor receptor 3 (HER3) is involved in the development of cancer resistance towards tyrosine kinase-targeted therapies. Several HER3‑targeting therapeutics are currently under clinical evaluation. Non-invasive imaging of HER3 expression could improve patient management. Affibody molecules are small engineered scaffold proteins demonstrating superior properties as targeting probes for molecular imaging compared with monoclonal antibodies. Feasibility of in vivo HER3 imaging using affibody molecules has been previously demonstrated...
October 11, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29039082/metal-based-proteasomal-deubiquitinase-inhibitors-as-potential-anticancer-agents
#16
Xin Chen, Qianqian Yang, Lu Xiao, Daolin Tang, Q Ping Dou, Jinbao Liu
Deubiquitinases (DUBs) play an important role in protein quality control in eukaryotic cells due to their ability to specifically remove ubiquitin from substrate proteins. Therefore, recent findings have focused on the relevance of DUBs to cancer development, and pharmacological intervention on these enzymes has become a promising strategy for cancer therapy. In particular, several DUBs are physically and/or functionally associated with the proteasome and are attractive targets for the development of novel anticancer drugs...
October 16, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29038381/has-molecular-imaging-delivered-to-drug-development
#17
REVIEW
Philip S Murphy, Neel Patel, Timothy J McCarthy
Pharmaceutical research and development requires a systematic interrogation of a candidate molecule through clinical studies. To ensure resources are spent on only the most promising molecules, early clinical studies must understand fundamental attributes of the drug candidate, including exposure at the target site, target binding and pharmacological response in disease. Molecular imaging has the potential to quantitatively characterize these properties in small, efficient clinical studies. Specific benefits of molecular imaging in this setting (compared to blood and tissue sampling) include non-invasiveness and the ability to survey the whole body temporally...
November 28, 2017: Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences
https://www.readbyqxmd.com/read/29037976/characterization-of-a-dengue-ns4b-inhibitor-originating-from-an-hcv-small-molecule-library
#18
Ilane Hernandez-Morales, Peggy Geluykens, Marleen Clynhens, Rudy Strijbos, Olivia Goethals, Sarah Megens, Nick Verheyen, Stefaan Last, David McGowan, Erwin Coesemans, Benoît De Boeck, Bart Stoops, Benoit Devogelaere, Frederik Pauwels, Koen Vandyck, Jan Martin Berke, Pierre Raboisson, Kenneth Simmen, Pedro Lory, Marnix Van Loock
Dengue is the most important mosquito-transmitted viral disease and a major global health concern. Over the last decade, dengue virus (DENV) drug discovery and development has intensified, however, this has not resulted in approved DENV-specific antiviral treatments yet. DENV and hepatitis C virus (HCV) belong to the same Flaviviridae family and, in contrast to DENV, antiviral treatments for HCV have been licensed. Therefore, applying the knowledge gained on anti-HCV drugs may foster the discovery and development of dengue antiviral drugs...
October 13, 2017: Antiviral Research
https://www.readbyqxmd.com/read/29037255/objective-measurement-and-clinical-significance-of-ido1-protein-in-hormone-receptor-positive-breast-cancer
#19
Daniel E Carvajal-Hausdorf, Nikita Mani, Vamsidhar Velcheti, Kurt A Schalper, David L Rimm
BACKGROUND: Immunostimulatory therapies targeting immune-suppressive pathways produce durable responses in advanced solid tumors. Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting oxidoreductase that catalyzes the degradation of tryptophan to kynurenine. IDO induces immune tolerance by downregulating CD8+ and effector CD4+ T cell responses. IDO1, the most active isoform, is expressed in diverse tumor types and can be targeted using small molecule inhibitors. We used an objective, in situ assay to measure IDO1 in a collection of hormone receptor-positive breast cancers (HR+ BC)...
October 17, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29037030/semisynthetic-bioluminescent-sensor-proteins-for-direct-detection-of-antibodies-and-small-molecules-in-solution
#20
Remco Arts, Susann Katrina Julie Ludwig, Benice C B van Gerven, Eva Magdalena Estirado, Lech-Gustav Milroy, Maarten Merkx
Single-step immunoassays that can be performed directly in solution are ideally suited for point-of-care diagnostics. Our group recently developed a new platform of bioluminescent sensor proteins (LUMABS; LUMinescent AntiBody Sensor) that allow antibody detection in blood plasma. Thus far, LUMABS has been limited to the detection of antibodies recognizing natural peptide epitopes. Here, we report the development of semisynthetic LUMABS sensors that recognize non-peptide epitopes. The non-natural amino acid para-azidophenylalanine was introduced at the position of the original antibody-recognition sites as a chemical handle to enable site-specific conjugation of synthetic epitope molecules coupled to a dibenzocylcooctyne moiety via strain-promoted click chemistry...
October 17, 2017: ACS Sensors
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