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https://www.readbyqxmd.com/read/29020637/combinatorial-microenvironments-impose-a-continuum-of-cellular-responses-to-a-single-pathway-targeted-anti-cancer-compound
#1
Chun-Han Lin, Tiina Jokela, Joe Gray, Mark A LaBarge
Tumor microenvironments are a driver of resistance to anti-cancer drugs. Dissecting cell-microenvironment interactions into tractable units of study presents a challenge. Here, we assess the impact of hundreds of tumor-inspired microenvironments, in parallel, on lapatinib responses in four cancer cell lines. Combinations of ECM and soluble factors were printed on stiffness-tunable substrata to generate a collection of controlled microenvironments in which to explore cell-based functional responses. Proliferation, HER2 protein expression and phosphorylation, and morphology were measured in single cells...
October 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28992441/mechanisms-of-tail-anchored-membrane-protein-targeting-and-insertion
#2
Un Seng Chio, Hyunju Cho, Shu-Ou Shan
Proper localization of membrane proteins is essential for the function of biological membranes and for the establishment of organelle identity within a cell. Molecular machineries that mediate membrane protein biogenesis need to not only achieve a high degree of efficiency and accuracy, but also prevent off-pathway aggregation events that can be detrimental to cells. The posttranslational targeting of tail-anchored proteins (TAs) provides tractable model systems to probe these fundamental issues. Recent advances in understanding TA-targeting pathways reveal sophisticated molecular machineries that drive and regulate these processes...
October 6, 2017: Annual Review of Cell and Developmental Biology
https://www.readbyqxmd.com/read/28989971/target-abundance-based-fitness-screening-tafis-facilitates-rapid-identification-of-target-specific-and-physiologically-active-chemical-probes
#3
Arielle Butts, Christian DeJarnette, Tracy L Peters, Josie E Parker, Morgan E Kerns, Karen E Eberle, Steve L Kelly, Glen E Palmer
Traditional approaches to drug discovery are frustratingly inefficient and have several key limitations that severely constrain our capacity to rapidly identify and develop novel experimental therapeutics. To address this, we have devised a second-generation target-based whole-cell screening assay based on the principles of competitive fitness, which can rapidly identify target-specific and physiologically active compounds. Briefly, strains expressing high, intermediate, and low levels of a preselected target protein are constructed, tagged with spectrally distinct fluorescent proteins (FPs), and pooled...
September 2017: MSphere
https://www.readbyqxmd.com/read/28938090/small-molecule-targets-in-immuno-oncology
#4
REVIEW
Dashyant Dhanak, James P Edwards, Ancho Nguyen, Peter J Tummino
Advances in understanding the role and molecular mechanisms underlying immune surveillance and control of (pre)malignancies is revolutionizing clinical practice in the treatment of cancer. Presently, multiple biologic drugs targeting the immune checkpoint proteins PD(L)1 or CTLA4 have been approved and/or are in advanced stages of clinical development for many cancers. In addition, combination therapy with these agents and other immunomodulators is being intensively explored with the aim of improving primary response rates or prolonging overall survival...
September 21, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28931678/ikk%C3%AE-mimetic-peptides-block-the-resistance-to-apoptosis-associated-with-kshv-infection
#5
Louise C Briggs, A W Edith Chan, Christopher A Davis, Nicholas Whitelock, Hajira A Hotiana, Mehdi Baratchian, Claire Bagnéris, David L Selwood, Mary K Collins, Tracey E Barrett
Primary effusion lymphoma (PEL) is a lymphogenic disorder associated with KSHV infection. Key to the survival and proliferation of PEL is the canonical NF-kB pathway that becomes constitutively activated following overexpression of the viral oncoprotein ks-vFLIP. This arises from its capacity to form a complex with the modulatory subunit of the IKK kinase, IKKγ (or NEMO) resulting in the overproduction of proteins that promote cellular survival and prevent apoptosis; both of which are important drivers of tumourigenesis...
September 20, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28920936/dopamine-induces-soluble-%C3%AE-synuclein-oligomers-and-nigrostriatal-degeneration
#6
Danielle E Mor, Elpida Tsika, Joseph R Mazzulli, Neal S Gould, Hanna Kim, Malcolm J Daniels, Shachee Doshi, Preetika Gupta, Jennifer L Grossman, Victor X Tan, Robert G Kalb, Kim A Caldwell, Guy A Caldwell, John H Wolfe, Harry Ischiropoulos
Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice...
September 18, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28919038/covalent-ligand-discovery-against-druggable-hotspots-targeted-by-anti-cancer-natural-products
#7
Elizabeth A Grossman, Carl C Ward, Jessica N Spradlin, Leslie A Bateman, Tucker R Huffman, David K Miyamoto, Jordan I Kleinman, Daniel K Nomura
Many natural products that show therapeutic activities are often difficult to synthesize or isolate and have unknown targets, hindering their development as drugs. Identifying druggable hotspots targeted by covalently acting anti-cancer natural products can enable pharmacological interrogation of these sites with more synthetically tractable compounds. Here, we used chemoproteomic platforms to discover that the anti-cancer natural product withaferin A targets C377 on the regulatory subunit PPP2R1A of the tumor-suppressor protein phosphatase 2A (PP2A) complex leading to activation of PP2A activity, inactivation of AKT, and impaired breast cancer cell proliferation...
September 11, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28902204/rational-design-and-structure-activity-relationship-studies-of-quercetin-amino-acid-hybrids-targeting-the-anti-apoptotic-protein-bcl-xl
#8
Tahsin F Kellici, Maria V Chatziathanasiadou, Min-Sung Lee, Nisar Sayyad, Elena G Geromichalou, Eirinaios I Vrettos, Antonis D Tsiailanis, Seung-Wook Chi, George D Geromichalos, Thomas Mavromoustakos, Andreas G Tzakos
Anti-apoptotic proteins, like the Bcl-2 family proteins, present an important therapeutic cancer drug target. Their activity is orchestrated through neutralization upon interaction of pro-apoptotic protein counterparts that leads to immortality of cancer cells. Therefore, generating compounds targeting these proteins is of immense therapeutic importance. Herein, Induced Fit Docking (IFD) and Molecular Dynamics (MD) simulations were performed to rationally design quercetin analogues that bind in the BH3 site of the Bcl-xL protein...
September 26, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28891297/validating-missing-proteins-in-human-sperm-cells-by-targeted-mass-spectrometry-and-antibody-based-methods
#9
Christine Carapito, Paula Duek, Charlotte Macron, Marine Seffals, Karine Rondel, Francois Delalande, Cecilia Lindskog, Thomas Freour, Yves Vandenbrouck, Lydie Lane, Charles Pineau
The present study is a contribution to the "neXt50 challenge", a coordinated effort across C-HPP teams to identify the 50 most tractable missing proteins (MPs) on each chromosome. We report the targeted search of 38 theoretically detectable MPs from chromosomes 2 and 14 in Triton X-100 soluble and insoluble sperm fractions from a total of 15 healthy donors. A targeted mass spectrometry-based strategy consisting in the development of LC-PRM assays (with heavy labeled synthetic peptides) targeting 92 proteotypic peptides of the 38 selected MPs was used...
September 11, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28882206/mechanism-based-strategies-for-structural-characterization-of-radical-sam-reaction-intermediates
#10
Katherine M Davis, Amie K Boal
X-ray crystallographic characterization of enzymes at different stages in their reaction cycles can provide unique insight into the reaction pathway, the number and type of intermediates formed, and their structural context. The known mechanistic diversity in the radical S-adenosylmethionine (SAM) superfamily of enzymes makes it an appealing target for such studies as more than 100,000 sequences have been identified to date with wide-ranging reactivities that share a pattern of complex radical-mediated chemistry...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28881357/a-novel-inhibitory-anti-invasive-mab-isolated-using-phenotypic-screening-highlights-anxa6-as-a-functionally-relevant-target-protein-in-pancreatic-cancer
#11
Dermot O'Sullivan, Paul Dowling, Helena Joyce, Edel McAuley, Andrew McCann, Michael Henry, Brianan McGovern, Paul Barham, Fergal C Kelleher, Jean Murphy, Susan Kennedy, Niall Swan, Michael Moriarty, Martin Clynes, Annemarie Larkin
BACKGROUND: Discovery and validation of new antibody tractable targets is critical for the development of new antibody therapeutics to address unmet needs in oncology. METHODS: A highly invasive clonal variant of the MDA-MB-435S cell line was used to generate monoclonal antibodies (MAbs), which were screened for anti-invasive activity against aggressive cancer cells in vitro. The molecular target of selected inhibitory MAb 9E1 was identified using immunoprecipitation/liquid chromatography-tandem mass spectrometry...
September 7, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28874467/an-evolutionarily-conserved-pathway-essential-for-orsay-virus-infection-of-caenorhabditis-elegans
#12
Hongbing Jiang, Kevin Chen, Luis E Sandoval, Christian Leung, David Wang
Many fundamental biological discoveries have been made in Caenorhabditis elegans The discovery of Orsay virus has enabled studies of host-virus interactions in this model organism. To identify host factors critical for Orsay virus infection, we designed a forward genetic screen that utilizes a virally induced green fluorescent protein (GFP) reporter. Following chemical mutagenesis, two Viro (virus induced reporter off) mutants that failed to express GFP were mapped to sid-3, a nonreceptor tyrosine kinase, and B0280...
September 5, 2017: MBio
https://www.readbyqxmd.com/read/28866639/overexpression-of-mirna-9-generates-muscle-hypercontraction-through-translational-repression-of-troponin-t-in-drosophila-melanogaster-indirect-flight-muscles
#13
Prasanna Katti, Divesh Thimmaya, Aditi Madan, Upendra Nongthomba
MicroRNAs (miRNAs) are small noncoding endogenous RNAs, typically 21-23 nucleotides long, that regulate gene expression, usually post-transcriptionally, by binding to the 3'-UTR of target mRNA, thus blocking translation. The expression of several miRNAs is significantly altered during cardiac hypertrophy, myocardial ischemia, fibrosis, heart failure, and other cardiac myopathies. Recent studies have implicated miRNA-9 (miR-9) in myocardial hypertrophy. However, a detailed mechanism remains obscure. In this study, we have addressed the roles of miR-9 in muscle development and function using a genetically tractable model system, the indirect flight muscles (IFMs) of Drosophila melanogaster Bioinformatics analysis identified 135 potential miR-9a targets, of which 27 genes were associated with Drosophila muscle development...
October 5, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28857552/precision-electrophile-tagging-in-caenorhabditis-elegans
#14
Marcus J C Long, Daniel A Urul, Shivansh Chawla, Hong-Yu Lin, Yi Zhao, Joseph A Haegele, Yiran Wang, Yimon Aye
Adduction of an electrophile to privileged sensor proteins and the resulting phenotypically dominant responses are increasingly appreciated as being essential for metazoan health. Functional similarities between the biological electrophiles and electrophilic pharmacophores commonly found in covalent drugs further fortify the translational relevance of these small-molecule signals. Genetically encodable or small-molecule-based fluorescent reporters and redox proteomics have revolutionized the observation and profiling of cellular redox states and electrophile-sensor proteins, respectively...
September 12, 2017: Biochemistry
https://www.readbyqxmd.com/read/28855394/an-in-vivo-genetic-screen-in-drosophila-identifies-the-orthologue-of-human-cancer-testis-gene-spo11-among-a-network-of-targets-to-inhibit-lethal-3-malignant-brain-tumour-growth
#15
Fabrizio Rossi, Cristina Molnar, Kazuya Hashiyama, Jan P Heinen, Judit Pampalona, Salud Llamazares, José Reina, Tomomi Hashiyama, Madhulika Rai, Giulia Pollarolo, Ismael Fernández-Hernández, Cayetano Gonzalez
Using transgenic RNAi technology, we have screened over 4000 genes to identify targets to inhibit malignant growth caused by the loss of function of lethal(3)malignant brain tumour in Drosophila in vivo We have identified 131 targets, which belong to a wide range of gene ontologies. Most of these target genes are not significantly overexpressed in mbt tumours hence showing that, rather counterintuitively, tumour-linked overexpression is not a good predictor of functional requirement. Moreover, we have found that most of the genes upregulated in mbt tumours remain overexpressed in tumour-suppressed double-mutant conditions, hence revealing that most of the tumour transcriptome signature is not necessarily correlated with malignant growth...
August 2017: Open Biology
https://www.readbyqxmd.com/read/28854942/the-biology-of-hepatocellular-carcinoma-implications-for-genomic-and-immune-therapies
#16
REVIEW
Galina Khemlina, Sadakatsu Ikeda, Razelle Kurzrock
Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is a leading cause of cancer-related death worldwide. It is highly refractory to most systemic therapies. Recently, significant progress has been made in uncovering genomic alterations in HCC, including potentially targetable aberrations. The most common molecular anomalies in this malignancy are mutations in the TERT promoter, TP53, CTNNB1, AXIN1, ARID1A, CDKN2A and CCND1 genes. PTEN loss at the protein level is also frequent. Genomic portfolios stratify by risk factors as follows: (i) CTNNB1 with alcoholic cirrhosis; and (ii) TP53 with hepatitis B virus-induced cirrhosis...
August 30, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28827530/development-of-a-comprehensive-set-of-tools-for-genome-engineering-in-a-cold-and-thermo-tolerant-kluyveromyces-marxianus-yeast-strain
#17
Yumiko Nambu-Nishida, Keiji Nishida, Tomohisa Hasunuma, Akihiko Kondo
Kluyveromyces marxianus, a non-conventional thermotolerant yeast, is potentially useful for production of ethanol and other products. This species has a strong tendency to randomly integrate transforming DNA fragments, making necessary the development of more precise methods for gene targeting. In this study, we first demonstrated that K. marxianus NBRC1777 is cold-tolerant, and then established a highly efficient and precise technique for gene editing by introducing genes encoding deaminase-mediated targeted point mutagenesis (Target-AID) and clustered regularly interspaced short palindromic repeats (CRISPR) associated proteins (CRISPR-Cas9)...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28820879/a-kinetic-view-of-gpcr-allostery-and-biased-agonism
#18
J Robert Lane, Lauren T May, Robert G Parton, Patrick M Sexton, Arthur Christopoulos
G-protein-coupled receptors (GPCRs) are one of the most tractable classes of drug targets. These dynamic proteins can adopt multiple active states that are linked to distinct functional outcomes. Such states can be differentially stabilized by ligands interacting with the endogenous agonist-binding orthosteric site and/or by ligands acting via spatially distinct allosteric sites, leading to the phenomena of 'biased agonism' or 'biased modulation'. These paradigms are having a major impact on modern drug discovery, but it is becoming increasingly apparent that 'kinetic context', at the level of both ligand-receptor and receptor-signal pathway kinetics, can have a profound impact on the observation and quantification of these phenomena...
August 18, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28808971/high-throughput-screening-for-identification-of-novel-innate-immune-activators
#19
Bryan J Gall, Victor R DeFilippis
Modern drug discovery has embraced in vitro platforms that enable investigation of large numbers of compounds within tractable timeframes and for feasible costs. These endeavors have been greatly aided in recent years by advances in molecular and cell-based methods such as gene delivery and editing technology, advanced imaging, robotics, and quantitative analysis. As such, the examination of phenotypic impacts of novel molecules may only be limited by the size of the compound collection. Innate immune signaling processes in mammalian cells are especially amenable to high-throughput screening platforms since the cellular responses elicited by their activation often result in high level transcription that can be harnessed in the form of bioluminescent or fluorescent signal...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28806897/evaluation-of-intrathecal-routes-of-administration-for-adeno-associated-viral-vectors-in-large-animals
#20
Christian Hinderer, Peter Bell, Nathan Katz, Charles H Vite, Jean-Pierre Louboutin, Erin Bote, Hongwei Yu, Yanqing Zhu, Margret L Casal, Jessica Bagel, Patricia O'Donnell, Ping Wang, Mark E Haskins, Tamara Goode, James M Wilson
Delivery of adeno-associated viral (AAV) vectors into the cerebrospinal fluid (CSF) can achieve gene transfer to cells throughout the brain and spinal cord, potentially making many neurological diseases tractable gene therapy targets. Identifying the optimal route of CSF access for intrathecal AAV delivery will be a critical step in translating this approach to clinical practice. We previously demonstrated that vector injection into the cisterna magna is a safe and effective method for intrathecal AAV delivery in nonhuman primates; however, this procedure is not commonly used in clinical practice...
October 3, 2017: Human Gene Therapy
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