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Targetted small molecules

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https://www.readbyqxmd.com/read/28212593/micrornas-and-endometriosis-distinguishing-drivers-from-passengers-in-disease-pathogenesis
#1
Warren B Nothnick
Endometriosis is a disease common in women of reproductive age, characterized by pelvic pain and infertility. Despite its prevalence, the factors and mechanisms which contribute to the development and survival of ectopic lesions remain uncertain. MicroRNAs (miRNAs) are small RNA molecules that regulate posttranscriptional gene regulation which have been proposed to contribute to the pathogenesis of many diseases including that of endometriosis. This review summarizes the results of initial studies describing differentially expressed miRNAs between endometriotic lesion tissue and eutopic endometrium...
February 17, 2017: Seminars in Reproductive Medicine
https://www.readbyqxmd.com/read/28211886/a-novel-approach-for-the-identification-of-efficient-combination-therapies-in-primary-human-acute-myeloid-leukemia-specimens
#2
I Baccelli, J Krosl, G Boucher, I Boivin, V-P Lavallée, J Hébert, S Lemieux, A Marinier, G Sauvageau
Appropriate culture methods for the interrogation of primary leukemic samples were hitherto lacking and current assays for compound screening are not adapted for large-scale investigation of synergistic combinations. In this study, we report a novel approach that efficiently distills synthetic lethal interactions between small molecules active on primary human acute myeloid leukemia (AML) specimens. In single-dose experiments and under culture conditions preserving leukemia stem cell activity, our strategy considerably reduces the number of tests needed for the identification of promising compound combinations...
February 17, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28211680/two-way-gold-nanoparticle-label-free-sensing-of-specific-sequence-and-small-molecule-targets-using-switchable-concatemers
#3
Longjiao Zhu, Xiangli Shao, Yunbo Luo, Kunlun Huang, Wentao Xu
A two-way colorimetric biosensor based on unmodified gold nanoparticles (GNPs) and a switchable double-stranded DNA (dsDNA) concatemer have been demonstrated. Two hairpin probes (H1&H2) were first designed that provided the fuels to assemble the dsDNA concatemers via hybridization chain reaction (HCR). A functional hairpin (FH) was rationally designed to recognize the target sequences. All the hairpins contained single-stranded DNA (ssDNA) loop and sticky-ends to prevent GNPs from salt-induced aggregation. In the presence of target sequence, the capture probe blocked in the FH recognizes the target to form a duplex DNA, which causes the release of the initiator probe by FH conformational change...
February 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28211573/the-cationic-small-molecule-gw4869-is-cytotoxic-to-high-phosphatidylserine-expressing-myeloma-cells
#4
Slavica Vuckovic, Kate Vandyke, David A Rickards, Padraig McCauley Winter, Simon H J Brown, Todd W Mitchell, Jun Liu, Jun Lu, Philip W Askenase, Elizabeth Yuriev, Ben Capuano, Paul A Ramsland, Geoffrey R Hill, Andrew C W Zannettino, Andrew T Hutchinson
We have discovered that a small cationic molecule, GW4869, is cytotoxic to a subset of myeloma cell lines and primary myeloma plasma cells. Biochemical analysis revealed that GW4869 binds to anionic phospholipids such as phosphatidylserine - a lipid normally confined to the intracellular side of the cell membrane. However, interestingly, phosphatidylserine was expressed on the surface of all myeloma cell lines tested (n = 12) and 9/15 primary myeloma samples. Notably, the level of phosphatidylserine expression correlated well with sensitivity to GW4869...
February 17, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28209987/targeting-phospholipase-d-in-cancer-infection-and-neurodegenerative-disorders
#5
REVIEW
H Alex Brown, Paul G Thomas, Craig W Lindsley
Lipid second messengers have essential roles in cellular function and contribute to the molecular mechanisms that underlie inflammation, malignant transformation, invasiveness, neurodegenerative disorders, and infectious and other pathophysiological processes. The phospholipase D (PLD) isoenzymes PLD1 and PLD2 are one of the major sources of signal-activated phosphatidic acid (PtdOH) generation downstream of a variety of cell-surface receptors, including G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and integrins...
February 17, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28209620/the-histone-methyltransferase-dot1l-promotes-neuroblastoma-by-regulating-gene-transcription
#6
Matthew Wong, Andrew El Tee, Giorgio Milazzo, Jessica L Bell, Rebecca C Poulos, Bernard Atmadibrata, Yuting Sun, Duohui Jing, Nicholas Ho, Dora Ling, Pei Yan Liu, Xu Dong Zhang, Stefan Hüttelmaier, Jason W H Wong, Jenny Wang, Patsie Polly, Giovanni Perini, Christopher J Scarlett, Tao Liu
Myc oncoproteins exert tumorigenic effects by regulating expression of target oncogenes. Histone H3 lysine 79 (H3K79) methylation at Myc-responsive elements of target gene promoters is a strict prerequisite for Myc-induced transcriptional activation, and DOT1L is the only known histone methyltransferase that catalyses H3K79 methylation. Here we show that N-Myc upregulatsd DOT1L mRNA and protein expression by binding to the DOT1L gene promoter. shRNA-mediated depletion of DOT1L reduced mRNA and protein expression of N-Myc target genes ODC1 and E2F2...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209619/lapatinib-resistance-in-breast-cancer-cells-is-accompanied-by-phosphorylation-mediated-reprogramming-of-glycolysis
#7
Benjamin Ruprecht, Esther A Zaal, Jana Zecha, Wei Wu, Celia R Berkers, Bernhard Kuster, Simone Lemeer
HER2/ERBB2-overexpressing breast cancers targeted effectively by the small molecule kinase inhibitor lapatinib frequently acquire resistance to this drug. In this study, we employed explorative mass spectrometry to profile proteomic, kinomic, and phosphoproteomic changes in an established model of lapatinib resistance to systematically investigate initial inhibitor response and subsequent reprogramming in resistance. The resulting dataset, which collectively contains quantitative data for >7,800 proteins, >300 protein kinases and >15,000 phosphopeptides, enabled deep insight into signaling recovery and molecular reprogramming upon resistance...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209615/targeted-degradation-of-bet-proteins-in-triple-negative-breast-cancer
#8
Longchuan Bai, Bing Zhou, Chao-Yie Yang, Jiao Ji, Donna McEachern, Sally Przybranowski, Hui Jiang, Jiantao Hu, Fuming Xu, Yujun Zhao, Liu Liu, Ester Fernandez-Salas, Jing Xu, Yali Dou, Bo Wen, Duxin Sun, Jennifer L Meagher, Jeanne Stuckey, Daniel F Hayes, Shunqiang Li, Matthew J Ellis, Shaomeng Wang
Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In this study, we report the development of a second-generation BET bromodomain (BRD) inhibitor, BETd-246, which exhibits superior selectivity, potency and antitumor activity. In human TNBC cells, BETd-246 induced degradation of BET transcription factors at low nanomolar concentrations within 1 hr of exposure, resulting in robust growth inhibition and apoptosis. BETd-246 was more potent and effective in TNBC cells than its parental BET inhibitor compound BETi-211...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209403/small-molecules-that-sabotage-bacterial-virulence
#9
REVIEW
Benjamin K Johnson, Robert B Abramovitch
The continued rise of antibiotic-resistant bacterial infections has motivated alternative strategies for target discovery and treatment of infections. Antivirulence therapies function through inhibition of in vivo required virulence factors to disarm the pathogen instead of directly targeting viability or growth. This approach to treating bacteria-mediated diseases may have advantages over traditional antibiotics because it targets factors specific for pathogenesis, potentially reducing selection for resistance and limiting collateral damage to the resident microbiota...
February 13, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28208648/n-butylidenephthalide-regulated-tumor-stem-cell-genes-ezh2-axl-and-reduced-its-migration-and-invasion-in-glioblastoma
#10
Ssu-Yin Yen, Hong-Meng Chuang, Mao-Hsuan Huang, Shinn-Zong Lin, Tzyy-Wen Chiou, Horng-Jyh Harn
Glioblastoma (GBM) is one of the most common and aggressive types of brain tumor. Due to its highly recurrent rate and poor prognosis, the overall survival time with this type of tumor is only 20-21 months. Recent knowledge suggests that its recurrence is in part due to the presence of cancer stem cells (CSCs), which display radioresistant, chemoresistant, self-renewal and tumorigenic potential. Enhancers of Zeste 2 (EZH2) and AXL receptor tyrosine kinase (AXL) are both highly expressed in GBM. Additionally, they are an essential regulator involved in CSCs maintenance, migration, invasion, epithelial-to-mesenchymal transition (EMT), stemness, metastasis and patient survival...
February 10, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28208642/photoluminescent-gold-nanoclusters-in-cancer-cells-cellular-uptake-toxicity-and-generation-of-reactive-oxygen-species
#11
Marija Matulionyte, Dominyka Dapkute, Laima Budenaite, Greta Jarockyte, Ricardas Rotomskis
In recent years, photoluminescent gold nanoclusters have attracted considerable interest in both fundamental biomedical research and practical applications. Due to their ultrasmall size, unique molecule-like optical properties, and facile synthesis gold nanoclusters have been considered very promising photoluminescent agents for biosensing, bioimaging, and targeted therapy. Yet, interaction of such ultra-small nanoclusters with cells and other biological objects remains poorly understood. Therefore, the assessment of the biocompatibility and potential toxicity of gold nanoclusters is of major importance before their clinical application...
February 10, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28208282/general-sensitive-detecting-strategy-of-ions-through-plasmonic-resonance-energy-transfer-from-gold-nanoparticles-to-rhodamine-spirolactam
#12
Ming Xuan Gao, Hong Yan Zou, Yuan Fang Li, Cheng Zhi Huang
Plasmonic resonance energy transfer (PRET), which occurs between the plasmonic nanoparticles and organic dyes, has significant potential in target sensing chemistry owing to its sensitivity at the single nanoparticle level. In this contribution, by using AuNPs, which has localized surface plasmonic resonance light scattering (LSPR-LS) around 550 nm, as the donor of PRET, a general sensitive detecting strategy of ions were developed. Targets can specifically react with a ring-close structured rhodamine spirolactam, which was prepared from rhodamines in the presence of different primary amine wherein the option of the primary amine is up to the targets, forming ring-open structured rhodamine spirolactam with the strong absorption around 550 nm...
February 7, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28208209/the-emergence-of-tnik-inhibitors-in-cancer-therapeutics
#13
REVIEW
Tesshi Yamada, Mari Masuda
The outcome of patients with metastatic colorectal cancer remains unsatisfactory. To improve patient prognosis, it will be necessary to identify new drug targets based on molecules that are essential for colorectal carcinogenesis, and to develop therapeutics that target such molecules. The great majority of colorectal cancers (>90%) have mutations in at least one Wnt signaling pathway gene. Aberrant activation of Wnt signaling is a major force driving colorectal carcinogenesis. Several therapeutics targeting Wnt pathway molecules, including porcupine, frizzled receptors, and tankyrases, have been developed, but none of them have yet been incorporated into clinical practice...
February 16, 2017: Cancer Science
https://www.readbyqxmd.com/read/28207249/convection-driven-pull-down-assays-in-nanoliter-droplets-using-scaffolded-aptamers
#14
Xiangmeng Qu, Hongbo Zhang, Hong Chen, Ali Aldalbahi, Li Li, Yang Tian, David A Weitz, Hao Pei
One of the great challenges in cellular studies is to develop a rapid and biocompatible analytical tool for single-cell analysis. We report a rapid, DNA nanostructure-supported aptamer pull-down (DNaPull) assay under convective flux in a glass capillary for analyzing contents of droplets with nano or picoliter volumes. We have demonstrated that the scaffolded aptamer can greatly improve the efficiency of target molecules' pull-down. The convective flux enables complete reaction in less than 5 min, which is an 18-fold improvement compared to purely diffusive flux (traditional model of stationary case)...
February 16, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28206986/in-situ-generated-d-peptidic-nanofibrils-as-multifaceted-apoptotic-inducers-to-target-cancer-cells
#15
Xuewen Du, Jie Zhou, Huainin Wang, Junfeng Shi, Yi Kuang, Wu Zeng, Zhimou Yang, Bing Xu
Nanofibrils of small molecules, as a new class of biofunctional entities, exhibit emergent properties for controlling cell fates, but the relevant mechanism remains to be elucidated and the in vivo effect has yet to be examined. Here, we show that D-peptide nanofibrils, generated by enzyme-instructed self-assembly (EISA), pleiotropically activate extrinsic death signaling for selectively killing cancer cells. Catalyzed by alkaline phosphatases and formed in situ on cancer cells, D-peptide nanofibrils present autocrine proapoptotic ligands to their cognate receptors in a juxtacrine manner, as well as directly cluster the death receptors...
February 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28205590/antifouling-potential-of-nature-inspired-sulfated-compounds
#16
Joana R Almeida, Marta Correia-da-Silva, Emília Sousa, Jorge Antunes, Madalena Pinto, Vitor Vasconcelos, Isabel Cunha
Natural products with a sulfated scaffold have emerged as antifouling agents with low or nontoxic effects to the environment. In this study 13 sulfated polyphenols were synthesized and tested for antifouling potential using the anti-settlement activity of mussel (Mytilus galloprovincialis) plantigrade post-larvae and bacterial growth inhibition towards four biofilm-forming bacterial strains. Results show that some of these Nature-inspired compounds were bioactive, particularly rutin persulfate (2), 3,6-bis(β-D-glucopyranosyl) xanthone persulfate (6), and gallic acid persulfate (12) against the settlement of plantigrades...
February 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28205403/functionalized-calix-4-arenes-as-potential-therapeutic-agents
#17
Muhammad Moazzam Naseer, Mukhtiar Ahmed, Shahid Hameed
Calixarenes, composed of phenolic units linked by methylene bridges at the 2,6-positions, represent a versatile class of macrocyclic compounds in supramolecular chemistry that can host small molecules or ions in their well-defined hydrophobic cavities. In recent years, it has been recognized that this class of compounds has the potential to serve as platform for the design of biological active compounds. Therefore, the calixarenes functionalized with different pharmacophoric groups have been synthesized as target structure by many researchers and were further evaluated for their biological activities...
February 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28205401/computer-aided-drug-design-to-explore-cyclodextrin-therapeutics-and-biomedical-applications
#18
Azizeh Abdolmaleki, Fatemeh Ghasemi, Jahan B Ghasemi
Cyclodextrin (CD) is a subset of the macrocyclic structural class, which is an important class of small organic agents that are useful functional excipients. They have wide range application possibilities in different fields of sciences such as material preparation, medicine, analytical chemistry, and separation processes. They are used widely in pharmaceutical formulations and drug delivery for increasing the water solubility of low soluble drugs and drug candidates. Due to the ring structure, they behave differently than smaller molecules and may be capable of hitting new classes of targets...
February 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28202766/inhibition-of-hiv-1-maturation-via-small-molecule-targeting-of-the-amino-terminal-domain-in-the-viral-capsid-protein
#19
Weifeng Wang, Jing Zhou, Upul D Halambage, Kellie A Jurado, Augusta V Jamin, Yujie Wang, Alan N Engelman, Christopher Aiken
The HIV-1 capsid protein is an attractive therapeutic target owing to its multifunctionality in virus replication and the high fitness cost of amino acid substitutions in capsid to HIV-1 infectivity. To date, small molecule inhibitors have been identified that inhibit HIV-1 capsid assembly and/or impair its function in target cells. Here we describe the mechanism of action of the previously reported capsid-targeting HIV-1 inhibitor, BI compound 1 (C1). We show that C1 acts during HIV-1 maturation to prevent assembly of a mature viral capsid...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28202663/translating-protein-phosphatase-research-into-treatments-for-neurodegenerative-diseases
#20
REVIEW
Jeyapriya R Sundaram, Irene C J Lee, Shirish Shenolikar
Many of the major neurodegenerative disorders are characterized by the accumulation of intracellular protein aggregates in neurons and other cells in brain, suggesting that errors in protein quality control mechanisms associated with the aging process play a critical role in the onset and progression of disease. The increased understanding of the unfolded protein response (UPR) signaling network and, more specifically, the structure and function of eIF2α phosphatases has enabled the development or discovery of small molecule inhibitors that show great promise in restoring protein homeostasis and ameliorating neuronal damage and death...
February 8, 2017: Biochemical Society Transactions
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