The histone lysine methyltransferase nuclear receptor-binding SET domain protein 2 (NSD2, also known as WHSC1/MMSET) is an epigenetic modifier and thought to play a driving role in oncogenesis. Both NSD2 overexpression and point mutations that increase its catalytic activity are associated with several human cancers. While NSD2 is an attractive therapeutic target, no potent, selective, and bioactive small molecule inhibitors of NSD2 have been reported to date, possibly due to the challenges of developing high-throughput assays for NSD2. Here, to establish a platform for the discovery and development of selective NSD2 inhibitors, we optimized and implemented multiple assays. We performed quantitative high-throughput screening with full-length wild-type NSD2 and a nucleosome substrate against a diverse collection of bioactive small molecules comprising 16,251 compounds. We further interrogated 174 inhibitory compounds identified in the primary screen with orthogonal and counter assays and with ...

The authors have retracted this article [1] because data shown in Figures 1-4 duplicate data in Figures 1, 2, 5, 6 and 8 in a previously published article by a different author group [2]. Yu Sun, Zhen Tian and Sui-Hui Li agree with this retraction. Xue-Feng Jiang and Shuang-Xi Zhu have not responded to correspondence from the editor or publisher about this retraction. The online version of this article contains the full text of the retracted article as electronic supplementary material. References [1] Xue-Feng Jiang, Zhen Tian, Shuang-Xi Zhu, Sui-Hui Li & Yu Sun. A novel small-molecule inhibitor suppresses colon cancer metastasis through inhibition of metastasis-associated in colon cancer-1 transcription. Invest New Drugs (2020). https://doi.org/10.1007/s10637-020-00957-8 [2] Manisha Juneja, Dennis Kobelt, Wolfgang Walther, Cynthia Voss, Janice Smith, Edgar Specker, Martin Neuenschwander, Björn-Oliver Gohlke, Mathias Dahlmann, Silke Radetzki, Robert Preissner, Jens Peter von Kries, Peter ...

Novartis Institutes for BioMedical Research, Cambridge, USA. Affinity proteomics and target identification for small molecule drug candidates. Affinity proteomics has become a valuable tool in preclinical small molecule drug discovery, in particular in the context of target identification and elucidation of the mechanism of action for drug candidates from phenotypic and pathway-centric approaches to drug discovery. Quantitative chemoproteomics, employing variations of a competition-based approach to small molecule affinity chromatography and mass spectrometry-based protein identification and quantitation, identifies cellular protein interactors and thus potential targets of drug candidates under conditions approximating the disease-relevant in vivo situation. Several examples will be presented and discussed in the context of orthogonal approaches to the generation of target hypotheses. On the other hand, the identification of protein-protein interactions using e.g. an affinity-tagged bait ...

At the end of the course, the student will know how organic chemistry, and in particular drug-like chemical diversity (assembled collections of different small organic molecules), can help in the identification and the characterization of new molecular targets; and will have acquired the necessary rudiments to understand the process of rational / computational design of small molecule modulators of either structurally characterized molecular targets (structure-based drug design, SBDD; fragment-based drug design, FBDD), or of non-structurally characterized molecular targets through their known ligands (ligand-based drug design, LBDD). Moreover, the student will acquire, besides the basic knowledge of NMR spectroscopy, also skills on different interaction techniques and learn how nuclear magnetic resonance can be important for the study of ligand-receptor interactions and for the development of new biologically active molecules ...

Current Research and Scholarly Interests We are interested in the structure, dynamics and function of eukaryotic transport proteins mediating ions and major nutrients crossing the membrane, the kinetics and regulation of transport processes, the catalytic mechanism of membrane embedded enzymes and the development of small molecule modulators based on the structure and function of membrane proteins. ...

Most drug discovery efforts focus on generating inhibitors leading to loss-of-function phenotypes. My lab has been focusing on discovering ways to activate enzymes leading to gain-of-function phenotypes. Many enzymes such as proteases and kinases are stored in dormant off forms that are subsequently activated through post-translational modification. Work will be presented for discovery of small molecule activators for the apoptotic proteases known as caspases, as well a Ser-Thr kinase PDK-1. Our group is also developing split-proteins that can be activated by orthogonal small molecule dimerizers to phenocopy the effects seen from the small molecule activators. Such protein activators allow one to ignite signaling from specific nodes and thus probe the sufficiency of enzyme activity to drive a cellular response. Protein activation, as opposed to inhibition, expands the landscape for drug discovery.. Citation Format: James A. Wells, Dennis Wolan, Julie Zorn, Debajyoti Datta, Daniel Gray, Jack ...

0009]These same Rho kinase inhibitors are cell permeable, and cause changes in cytoskeletal function and cell behavior consistent with loss of Rho kinase activity, similar to effects of the trans-dominant inhibitory mutants. Effects have been observed both in cultured cells in vitro and in physiologically responsive tissues in vivo [Nagumo, H. et al., 2000, Am J Physiol Cell Physiol. 278:C57-C65; Sinnett-Smith, J. et al., 2001, Exp Cell Res. 266:292-302; Chrissobolis, S. and Sobey, C. G., 2001, Circ Res. 88:774-779; Honjo, M. et al., 2001, Invest Ophthalmol Vis Sci. 42:137-144; Takahara, A. et al., 2003, Eur J Pharmacol. 460:51-57; Fournier, A. E. et al., 2003, J Neurosci. 23:1416-1423; Rikitake, Y. et al., 2005, Stroke. 36:2251-2257; Slotta, J. E. et al. 2006, Inflamm Res. 55:364-367; Ying, H. et al., 2006, Mol Cancer Ther. 5:2158-2164]. The correlation between small molecule inhibition of Rho kinases and changes in cell behavior both in vitro and in vivo (e.g., vascular smooth muscle ...

Discussions of therapeutic suppression of hedgehog (Hh) signaling almost exclusively focus on receptor antagonism; however, hedgehogs biosynthesis represents a unique and potentially targetable aspect of this oncogenic signaling pathway. Here, we review a key biosynthetic step called cholesterolysis from the perspectives of structure/function and small molecule inhibition. Cholesterolysis, also called cholesteroylation, generates cholesterol-modified Hh ligand via autoprocessing of a hedgehog precursor protein. Post-translational modification by cholesterol appears to be restricted to proteins in the hedgehog family. The transformation is essential for Hh biological activity and upstream of signaling events. Despite its decisive role in generating ligand, cholesterolysis remains conspicuously unexplored as a therapeutic target.

TY - JOUR. T1 - Glioblastoma cell growth is suppressed by disruption of fibroblast growth factor pathway signaling. AU - Loilome, Watcharin. AU - Joshi, Avadhut D.. AU - ap Rhys, Colette M.J.. AU - Piccirillo, Sara. AU - Vescovi, Angelo. AU - Gallia, Gary L.. AU - Riggins, Gregory J.. PY - 2009/4/8. Y1 - 2009/4/8. N2 - The Fibroblast Growth Factor (FGF) signaling pathway is reported to stimulate glioblastoma (GBM) growth. In this work we evaluated the effect of FGF2, FGF receptor (FGFR), and small molecule inhibition on GBM cells grown in traditional media, or cultured directly in stem-cell media. These lines each expressed the FGFR1, FGFR3 and FGFR4 receptors. Addition of FGF2 ligand showed significant growth stimulation in 8 of 10 cell lines. Disruption of FGF signaling by a neutralizing FGF2 monoclonal antibody and FGFR1 suppression by RNA interference both partially inhibited cell proliferation. Growth inhibition was temporally correlated with a reduction in MAPK signaling. A receptor ...

Flavia Amadeu de Oliveira, Ph.D.. I am pleased and delighted for being the recipient of ASBMR Fund for Research and Education Research Grant 2019. I am currently investigating the molecular targets driving osteosarcoma metastasis, focusing specifically on FGFR and mTOR signalling. My work has so far demonstrated that small molecule inhibition of these pathways could serve as a potential therapy for inhibiting metastasis in osteosarcoma patients. The transcriptional and biochemical mechanisms underlying this effect are not known and therefore this award will help me to take a global approach through analysing and bridging together large genomic and proteomic data sets. Well-established training courses will provide me with additional expertise which I will be using for current and future research projects with a liberty to analyse data based on my independent biological questions. This award will be used in part to obtain bulk RNA-seq and proteomic data of tumour cells excised from different ...

Poly-α2,8-sialic acid (PSA) has been implicated in numerous normal and pathological processes, including development, neuronal plasticity, and tumor metastasis. We report that cell surface PSA expression can be reversibly inhibited by a small molecule,N-butanoylmannosamine (ManBut). Inhibition occurs through a metabolic mechanism in which ManBut is converted to unnatural sialic acid derivatives that effectively act as chain terminators during cellular PSA biosynthesis. N-Propanoylmannosamine (ManProp), which differs from ManBut by a single methylene group, did not inhibit PSA biosynthesis. Modulation of PSA expression by chemical means has a role complementary to genetic and biochemical approaches in the study of complex PSA-mediated events. ...

BACKGROUND: 15-Hydroxyprostaglandin dehydrogenase (15-PGDH, EC 1.1.1.141) is the key enzyme for the inactivation of prostaglandins, regulating processes such as inflammation or proliferation. The anabolic pathways of prostaglandins, especially with respect to regulation of the cyclooxygenase (COX) enzymes have been studied in detail; however, little is known about downstream events including functional interaction of prostaglandin-processing and -metabolizing enzymes. High-affinity probes for 15-PGDH will, therefore, represent important tools for further studies. PRINCIPAL FINDINGS: To identify novel high-affinity inhibitors of 15-PGDH we performed a quantitative high-throughput screen (qHTS) by testing |160 thousand compounds in a concentration-response format and identified compounds that act as noncompetitive inhibitors as well as a competitive inhibitor, with nanomolar affinity. Both types of inhibitors caused strong thermal stabilization of the enzyme, with cofactor dependencies correlating with

Video articles in JoVE about embryo mammalian include Isolation and Culture of Embryonic Mouse Neural Stem Cells, Isolation of Embryonic Ventricular Endothelial Cells, Genetic Manipulation of the Mouse Developing Hypothalamus through In utero Electroporation, Separation of Mouse Embryonic Facial Ectoderm and Mesenchyme.

1. Lineage specific transcription factors.. We are using genetic and biochemical approaches to define the molecular mechanisms through which lineage-specific transcriptional regulators orchestrate self-renewal and differentiation, focussing on SOX, FOX and bHLH families. These lie at the heart of cell fate decision-making by neural stem and progenitor cells during development and within brain tumours.. 2. Chemical and genetic screening. We are carrying out image-based small molecule screens to search for new agents and pathways that can modulate self-renewal and differentiation of normal and glioblastoma-derived neural stem cells. 3. Epigenetic programming and reprogramming. We are investigating whether changes to the epigenome within glioblastoma-derived cancer stem cells enable suppression of malignant properties. We are using both direct differentiation as well as nuclear reprogramming strategies to test this.. 4. Genome editing. Designer transcription factors and nucleases (TALENs or ...

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0031]The procedure for molecular docking involves: 1) selection of structural pockets in PKCiota suitable for interactions with drug-like small compounds, and 2) molecular docking simulations where each one of approximately 300,000 small compounds (MW,500) is positioned in the selected structural pocket and scored based on predicted polar (e.g., H bond) and non-polar (e.g. Van der Waals) interactions. The top 30 scoring compounds for each selected structural pocket were obtained for use in functional assays. Docking calculations were performed with the Oct. 15, 2002 development version of DOCKv5.1.0. molecular docking calculations The coordinates for the crystal structure PKC, PDB code 1ZRZ, was used. The molecular surface of the structure was explored using sets of spheres to describe potential binding pockets. The spheres literally fill in the available pocket spaces where a ligand might be able to form a complex. DOCK uses the spheres as a guide to search for orientations of each compound ...

Mimicking the BH3 domain to kill cancers is a strategy that is presently being explored in the development of Bcl2 inhibitors as anticancer drugs (40, 41). By binding to the hydrophobic cleft of Bcl2/Bcl-XL, the BH3 mimetics function as competitive inhibitors (18, 40). Three small-molecule Bcl2 inhibitors, including gossypol (AT-101), obatoclax (GX15-070), and ABT-263, are in clinical trials (phase I∼II; refs. 40, 41). Gossypol and obatoclax are BH3 mimetics that act as pan-Bcl2 inhibitors (12, 41). However, gossypol and obatoclax are not entirely dependent on Bax and Bak for apoptosis induction and toxicity to normal cells (40, 42). In contrast, the Bad BH3 mimetic ABT-737 was ineffective in inducing apoptosis in cells doubly deficient in Bax and Bak, indicating that its mechanism of action may be predominantly through the Bcl2 family (40, 43). ABT-737 selectively binds to Bcl2, Bcl-XL, and Bcl-W but not Mcl-1 and Bfl-1/A1 (18). However, ABT-737 resistance can be caused by expression of Mcl-1 ...

With more than 10 years of accumulation, KBP has built a small molecule compound library with over 3,000,000 chemical compounds consisting of compounds designed and synthesized by KBP with unique chemical structures and high potency, compounds synthesized based on different core structures that cover almost all known core structures, and a natural product library of compounds extracted from plants, marine organisms and microorganisms.. Coupled with our bio-evaluation technology platform, the compound library enables KBP to identify and progress unique drugs that fit global unmet medical need quickly and efficiently.. Over 100 lead compounds have been screened from the library, and 3 compounds have entered into international clinical development.. ...

Marine soft corals are known to produce a wide array of secondary metabolites, particularly diterpenoids and steroids, and often characterized by uncommon structural features and potent bioactivities. The remarkable abundance and diversity of bioactive small molecule which have been isolated from soft corals have made these organisms an important source of new drug candidates for human diseases, particularly for their anti-inflammatory activity. In this paper, the authors reported anti-inflammatory marine natural products isolated from diverse species of soft corals determined in vitro by their inhibition of lipopolysaccharide-induced expression of inducible NO synthase and cyclooxygenase-2 in murine macrophage cells (RAW 264.7 ...

CGRP receptor small molecule antagonists. Several small molecule antagonists have been shown to block the binding of CGRP to its receptors. They are chemically un-related but they all do the same job and collectively referred as gepants. All gepants that have been tested to date are effective in patients with migraine (3-5). Olcegepant was the first to be discovered but since then others have been successfully tested - telcagepant, ubrogepant, MK-3207, BI 44370 TA and BMS-927711. However, further development of gepants has been clouded by the discovery of liver toxicity with long term use of the earlier gepants. Ubrogepant and atogepant are newly developed gepants that are chemically different from telcagepant and the other gepants. Ubrogepant has completed phase IIb testing and is being evaluated in phase III trials for acute relief of migraine. To date, results indicate that ubrogepant has good efficacy, comparable to that of triptans, with no incidence of elevated liver enzymes or other ...

Bacterial infections are increasingly difficult to treat owing to the spread of antibiotic resistance. A major concern is Gram-negative bacteria, for which the discovery of new antimicrobial drugs has been particularly scarce. In an effort to accelerate early steps in drug discovery, the EU-funded AEROPATH project aims to identify novel targets in the opportunistic pathogen Pseudomonas aeruginosa by applying a multidisciplinary approach encompassing target validation, structural characterization, assay development and hit identification from small-molecule libraries. Here, the strategies used for target selection are described and progress in protein production and structure analysis is reported. Of the 102 selected targets, 84 could be produced in soluble form and the de novo structures of 39 proteins have been determined. The crystal structures of eight of these targets, ranging from hypothetical unknown proteins to metabolic enzymes from different functional classes (PA1645, PA1648, PA2169, ...

Rheumatoid arthritis patients who do not respond to treatment with biologic therapies may find relief in baricitinib, a new small molecule drug, according to the results of a phase III study published in The New England Journal of Medicine online, 31 March 2016 ...

Chemical library technologies have brought about dramatic changes in the drug discovery process, and, though still evolving, they have become an integral part of ongoing drug discovery research. In Ch

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Observed deficits in protein phosphatase 2A (PP2A) function in a variety of human cancers have stimulated drug discovery efforts aimed at restoring PP2A function to inhibit tumor growth. Work published by Sangodkar et al. in this issue of the JCI describes the characterization of orally available small molecule activators of PP2A (SMAPs). These SMAPs attenuated mitogenic signaling and triggered apoptosis in KRAS-mutant lung cancer cells and inhibited tumor growth in murine models. Tumors with mutations in the SMAP-binding site of the PP2A A subunit displayed resistance to SMAPs. Future studies that identify the PP2A-regulated events targeted by SMAPs should guide critical decisions about which cancers might be best treated with these molecules. This study provides encouraging evidence in favor of SMAPs as potential anticancer drugs ...

Breaking news and analysis of the global biotechnology, pharmaceutical, medical device and medical technology sectors. In-depth coverage of innovation, business, financing, regulation, science, product development, clinical trials and more

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The Wnt/ß-catenin signaling pathway controls important cellular events during development and often contributes to disease when dysregulated. Using high throughput screening we have identified a new small molecule inhibitor of Wnt/ß-catenin signaling, WIKI4. WIKI4 inhibits expression of ß-catenin target genes and cellular responses to Wnt/ß-catenin signaling in cancer cell lines as well as in human embryonic stem cells. Furthermore, we demonstrate that WIKI4 mediates its effects on Wnt/ß-catenin signaling by inhibiting the enzymatic activity of TNKS2, a regulator of AXIN ubiquitylation and degradation. While TNKS has previously been shown to be the target of small molecule inhibitors of Wnt/ß-catenin signaling, WIKI4 is structurally distinct from previously identified TNKS inhibitors.

The advent of Gleevec® (imatinib) less than 10 years ago was a landmark for utilizing small molecule compounds as kinase inhibitor drugs (1-3). This type of drug is usually directed against one specific kinase whose malfunctioning plays a key role in the given disease. Generally these drugs are thought to be selective, easy to modify, and effective. As the molecular principles of various diseases are better understood, kinase inhibitors are being developed in various fields with cancer remaining the predominant one (4). Kinase inhibitor compounds constitute about 30% of all drug development programs in the pharmaceutical industry (5).. Kinase inhibitor drugs are typically developed with a targeted and rational strategy, often focusing on a kinase known to be involved in the etiology of a disease. Large libraries of chemical compounds, for example ATP analogs, are screened in vitro against the activity of this kinase, and their effects on a panel of manually selected kinases with similar ...

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Plans to almost double access to free early learning and childcare in one early years centre in Prestwick have been agreed by South Ayrshire Council. The pilot project forms part of a modernisation pa

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Mr Smith said: The picture for Glasgow Prestwick Airport is a positive one - we believe our passenger numbers have bottomed out and are on the up again, cargo income is consistent in spite of changes in the wider market, military income is growing, property occupancy are at an all-time high and early indications for the last financial year show that our losses are less than predicted.. The turnaround will be challenging and will take time, but it has started and this plan will build upon this.. The Scottish Government has always stated that they would like to return the business to the private sector and this is a fundamental pillar of our plan.. We are working to make the business an attractive prospect for a private investor to come in and build upon this strategy - someone that can bring in additional funds to upgrade our infrastructure and facilities and attract even more business.. If we are able to do this, we could speed up our turnaround.. Airport chairman Andrew Miller said the ...

...BOSTON Mass. (Feb. 24 2008)Why do nearly 1 million people taking cho...A new chemical toolkit provides the first clinical explanation for the...A research team led by Harvard Medical School assistant professor and ...Over the last few decades mitochondria have increasingly been underst...,New,chemical,tool,kit,manipulates,mitochondria,,reveals,insights,into,drug,toxicity,biological,biology news articles,biology news today,latest biology news,current biology news,biology newsletters

Principal Research Interests: medicinal chemistry and drug discovery, targeted anti-cancer agents.. The medicinal chemistry team (C Cano, BT Golding, IR Hardcastle, and M Waring) is part of the Drug Discovery Group within the NICR. Working closely with basic cancer biologists, structural biologists, pharmacologists, imaging specialists, and clinical scientists, the overall aim of the programme is to discover novel small-molecule inhibitors of cancer targets which can be developed into new treatments for cancer patients. Targets are selected based on an understanding of the underlying cancer biology and their clinical relevance. Current projects include the discovery of small-molecule MDM2-p53 protein protein interactions, the discovery of small-molecule ERK5 inhibitors, and hit-discovery studies for other novel cancer targets.. Contemporary, medicinal chemistry methods are used in all projects. including high throughput screening to identify hit compounds (through external collaborations), and ...

Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, Jin L, Boss O, Perni RB, Vu CB, Bemis JE, Xie R, Disch JS, Ng PY, Nunes JJ, Lynch AV, Yang H, Galonek H, Israelian K, Choy W, Iffland A, Lavu S, Medvedik O, Sinclair DA, Olefsky JM, Jirousek MR, Elliott PJ, Westphal CH. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007;450:712-16 ...

It is an interdisciplinary section devoted to all aspects of chemical biology, a rapidly growing field at the interface of chemistry and biology as well as related biomedical fields. The section offers a peer-reviewed and open access publication option to chemists, biologists and other researchers that develop and apply chemical tools to investigate biological systems and processes. Chemical Biology covers advances in a wide range of topics in the field, from new molecular tools and techniques, to their applications to address biological questions at the molecular or cellular level. The focus is on molecules and methods used to identify, visualize, probe or validate the biological functions of small molecules or biomolecules and their biological pathways. Examples include: the design, synthesis, and use of novel molecular systems as tools to study biology; the use of special chemical techniques, such as click chemistry and molecular imaging, to study the actions of small and large biomolecules ...

Buy and find information on Product Number c08885, 5-amino-2,4,6-triiodoisophthalic acid, CAS Number 35453-19-1, 8,8g, We sell fine chemicals, building blocks and small molecule compounds to the pharmaceutical, drug discovery, agrochemical and biotechnology companies, university or institute scientists.

This work proposes to use the marine algal toxin yessotoxin (YTX) to establish reference model experiments to explore medically valuable effects from induction of multiple cell death pathways. YTX is one of few toxins reported to make such induction. It is a small molecule compound which at low concentrations can induce apoptosis in primary cultures, many types of cells and cell lines. It can also induce a non-apoptotic form of programmed cell death in BC3H1 myoblast cell lines. The present contribution reviews arguments that this type of induction may have principal interest outside this particular example. One principal effect of medical interest may be that cancer cells will not so easily adapt to the synergistic effects from induction of more than one death pathway as compared to induction of only apoptosis.

Giving solutions to the problems of crystallization and crystallography. Protein and small molecule compounds crystallization, Structural Crystallography, Space logistic support for crystallization experiments, tailor-made crystals of high purity.

Giving solutions to the problems of crystallization and crystallography. Protein and small molecule compounds crystallization, Structural Crystallography, Space logistic support for crystallization experiments, tailor-made crystals of high purity.

H3 Biomedicine, a member of Eisais global Oncology Business Group, has received orphan drug designation from the US Food and Drug Administration (FDA) for its H3B-8800, a clinical compound used to treat patients with acute myelogenous leukaemia (AML) and chronic myelomonocytic leukaemia (CMML).. H3 Biomedicine is a clinical stage biopharmaceutical company that focuses on the discovery and development of precision medicines for oncology.. H3B-8800 is a potent, selective and orally bioavailable small molecule modulator of wild-type and mutant SF3b complexes.. H3 Biomedicine president and CEO Dr Markus Warmuth said: Receiving the orphan drug designation for H3B-8800 is a critical milestone for H3s ongoing cancer genomics driven drug discovery programme.. ...

AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance by sensing and responding to increases in AMP/ADP concentration relative to ATP. Binding of AMP causes allosteric activation of the enzyme and binding of either AMP or ADP promotes and maintains the phosphor …

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), yet 40-50% of patients will eventually succumb to their disease demonstrating a pressing need for novel therapeutic options. Gene expression profiling has identified messenger RNAs that lead to transformation, but critical events transforming cells are normally executed by kinases. Therefore, we hypothesized that previously unrecognized kinases may contribute to DLBCL pathogenesis. We performed the first comprehensive analysis of global kinase activity in DLBCL, to identify novel therapeutic targets, and discovered that Germinal Center Kinase (GCK) was extensively activated. GCK RNA interference and small molecule inhibition induced cell cycle arrest and apoptosis in DLBCL cell lines and primary tumors in vitro and decreased the tumor growth rate in vivo, resulting in a significantly extended lifespan of mice bearing DLBCL xenografts. GCK expression was also linked to adverse clinical outcome in a ...

Since oxidative cellular damage contributes to the development of cancers, heart disease and ageing, the synthesis of antioxidative agents which are able to either prevent or mitigate oxidative stress to cells is an important area of investigation. Combinatorial chemistry has had a profound impact on the discovery and optimisation of potential lead compounds, especially in the medicinal field. This review details recent examples of combinatorial chemistry dealing with the synthesis of novel antioxidants with an emphasis on solid phase compound synthesis and parallel library synthesis.. Full text not available from this repository.. ...

View more ,The synthesis of saccharin (1,2-benzisothiazol-3-one-1,1-dioxide) derivatives substituted on the benzene ring has seen limited development despite the longevity of this compounds use as an artificial sweetener. This type of saccharin derivative would however present attractive properties for the development of new bioactive, drug-like small molecule compounds. Here we report the derivatisation of the benzene ring of saccharin using Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC) to synthesise a diverse library of novel saccharin-1,2,3-triazole conjugates. All library compounds retain the capability for interactions with biomolecules via the unmodified sulfonamide and lactam groups of the parent saccharin core heterocycle. The compounds also encompass alternate orientations of the 1,2,3-triazole heterocycle, thus further adding diversity to the potential hydrogen bonding interactions of these compounds with biomolecules of therapeutic interest. Our findings demonstrate that ...

Prof Paranagamas overarching research interests revolve around bioactive natural products from plant associated fungi and endolichenic fungi. Recently she has initiated a new research program in examining bioactive compounds from endolichenic fungi in mangroves in Sri Lanka. Bioactive small molecules are monitored using anticancer, antifungal, antibacterial, antioxidant, anti-inflammatory, anti-diabetics, anti-lipase and insecticidal bioassays. She has established foreign collaboration with Prof. Leslie Gunatilaka from University of Arizona and Dr. Gothamie Weerakoon from The Field Museum, Chicago. Moreover her current research interests also include development of value added products from by-products of fruits and vegetables, development of Nutraceuticals from local natural resources, development of bio-pesticides from semiochemicals to control agricultural pests in Sri Lanka and nutritional analysis of traditional food varieties. She is interested in conducting research on toxic trace ...

Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes ...

Isogenica, Cambridge UK and Imperial College London secure funding from UKs Technology Strategy Board to develop gene library synthesis for synthetic

The present invention provides a method of screening for compounds which affect the processing of EphA4 by .gamma.-secretase, which includes the following steps: (i) contacting a first biological composition containing .gamma.-secretase or a biologically active fragment thereof with a second biological composition containing EphA4 in the presence and absence of a candidate compound; (ii) measuring the cleavage of the EphA4 in the presence and absence of the candidate compound; (iii) selecting those candidate compounds which affect the cleavage of the EphA4 by .gamma.-secretase; and (iv) identifying the candidate compounds selected in step (iii) as compounds which affect the processing of EphA4 by .gamma.-secretase.

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Table of Contents Describing Detail Research Report:. 1. Small Molecule Cancer Drug Market Report Overview. 2 Global Small Molecule Cancer Drug Growth Trends. 3. Small Molecule Cancer Drug Market Share by Manufacturers. 4. Small Molecule Cancer Drug Market Size by Type. 5. Small Molecule Cancer Drug Market Size by Application. 6. Small Molecule Cancer Drug Production by Regions. 7 Perfusion Imaging by Regions. 8. Small Molecule Cancer Drug Company Profiles. 9. Small Molecule Cancer Drug Market Forecast 2019-2026.. 10 Value Chain and Sales Channels Analysis. 11 Opportunities & Challenges, Threat and Affecting Factors. 12 Key Findings. 13 Appendix. Want Every Element Covered in the Small Molecule Cancer Drug Report? Ask For Detailed Table Of Content Here. https://www.globalmarketers.biz/report/life-sciences/global-small-molecule-cancer-drug-industry-market-research-report/4654 #table_of_contents. Reasons to Buy our Report:. 1. The report offers an analysis of competitive landscape.. 2. T make ...

About the Metabolomics Workbench: The National Institutes of Health (NIH) Common Fund Metabolomics Program was developed with the goal of increasing national capacity in metabolomics by supporting the development of next generation technologies, providing training and mentoring opportunities, increasing the inventory and availability of high quality reference standards, and promoting data sharing and collaboration. In support of this effort, the Metabolomics Programs Data Repository and Coordinating Center (DRCC), housed at the San Diego Supercomputer Center (SDSC), University of California, San Diego, has developed the Metabolomics Workbench. The Metabolomics Workbench will serve as a national and international repository for metabolomics data and metadata and will provide analysis tools and access to metabolite standards, protocols, tutorials, training, and more.

Celgene Anti-Inflammatory Compounds are small molecule compounds that inhibit the production of multiple pro-inflammatory mediators and molecules created or released by the immune system.

Abstract: Persistent activation of the signal transducer and activator of transcription 3 (STAT3) signalling has been linked to oncogenesis and the development of chemotherapy resistance in glioblastoma and other cancers. Inhibition of the STAT3 pathway thus represents an attractive therapeutic approach for cancer. In this study we investigated the inhibitory effects of a small molecule compound known as LLL-3 which is a structural analogue of the earlier reported STAT3 inhibitor STA-21 on the cell viability of human glioblastoma cells U87 U373 and U251 expressing constitutively activated STAT3. We also investigated the inhibitory effects of LLL-3 on U87 glioblastoma cell growth in a mouse tumour model as well as the impact it had on the survival time of the treated mice. We observed that LLL-3 inhibited STAT3-dependent transcriptional and DNA binding activities. LLL-3 also inhibited viability of U87 U373 and U251 glioblastoma cells as well as induced apoptosis of these glioblastoma cell lines ...

The functionality of all cells depends critically on protein-protein interactions (PPI), particularly on the formation of multi-protein complexes. The traditional methods for studying PPIs rely on steady-state analysis of protein complexes that have been extracted from their native cellular environment. This is a significant shortcoming for functional studies. We use Protein-fragment Complementation Assays (PCA), a novel group of methods that allows studying dynamics of PPIs in live cells, to understand basic molecular mechanisms involved in pathophysiology of neurodegenerative diseases. Currently, our focus is on normal cellular regulation of β-amyloid precursor protein (APP) and microtubule-associated protein Tau, molecules that are involved in amyloid plaque and neurofibrillary pathologies in AD, respectively. Our technology platform allows various types of approaches, including mechanistic studies and screening of novel small-molecule modulators of PPIs ...

ACH-3102 is a structurally distinct small molecule compound that has demonstrated potent inhibition of the NS5A protein across all genotypes of HCV in preclinical studies. Furthermore, the unique chemical structure of ACH-3102 has resulted in enhanced potency in vitro against resistant mutants that have emerged during clinical studies with first generation NS5A inhibitors.. We are very pleased with the granting of a Fast Track designation for ACH-3102, which we believe highlights this second-generation NS5A inhibitors attributes that include pan-genotypic coverage of HCV and potential for maintained activity against NS5A mutant strains of HCV, commented Michael Kishbauch, President and Chief Executive Officer of Achillion. We are excited to leverage the superior profile of ACH-3102 in combination with our Phase 2 protease inhibitor, ACH-1625, as we seek to create an optimized, potentially best-in-class potent, well-tolerated, once-daily regimen to treat HCV, which will enter combination ...

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. Although chemotherapy in combination with anti-CD20 antibodies results in a cure rate of 60-70 %, novel treatment approaches are warranted for the remaining patients. The insulin-like growth factor-1 receptor (IGF-1R) and its principal ligands IGF-1 and IGF-2 have been suggested to play pivotal roles in different cancers. However, in DLBCL the importance of this system is less well understood. To assess whether interference with IGF-1R-mediated signaling may represent a therapeutic option for this malignancy, we used a panel of eight DLBCL cell lines together with primary tumor cells derived from lymph nodes in four DLBCL patients. The cells were treated with the cyclolignan picropodophyllin (PPP), a small molecule compound initially described to selectively inhibit the IGF-1R. PPP dose-dependently inhibited proliferation/survival in all cell lines and primary cell preparations. In parallel experiments, the IGF-1R ...

FUN_09: Evaluation of the Inhibitory Activity of Small Molecule Compounds Against Rickettsia prowazekii Methionine Aminopeptidase (MetAp) using in vitro & in vivo Assays.

DIM (3,3-diindolylmethane), a small molecule compound, is a proposed cancer preventive agent that can be safely administered to humans in repeated doses. We report that administration of DIM in a multidose schedule protected rodents against lethal doses of total body irradiation up to 13 Gy, whethe …

Myotonic Dystrophy type 1 (DM1) is an inherited disease seen as a IL18BP antibody the shortcoming to relax contracted muscles. concentrations (nanomolar) in comparison to its make use of as an over-all transcription PF-04691502 inhibitor or chemotherapeutic. ActD also considerably reversed DM1-linked splicing defects within a DM1 mouse model and do so inside the presently approved individual treatment range. RNA-seq analyses showed that low PF-04691502 concentrations of ActD didnt inhibit transcription within a DM1 PF-04691502 mouse super model tiffany livingston globally. These total results indicate that transcription inhibition of CTG expansions is a PF-04691502 appealing remedy approach for DM1. Launch Myotonic dystrophy (DM) the most frequent type of adult starting point muscular dystrophy is normally an illness seen as a (however not limited by) myotonia muscles wasting insulin level of resistance cardiomyopathy and cognitive dysfunctions (Ranum et al. 2006 Cho et al. 2007 DM provides two ...

The aim of the 6th RSC-BMCS Fragment-based Drug Discovery meeting will be to continue the focus on case studies in Fragment-based Drug Discovery that have delivered compounds to late stage medicinal chemistry, preclinical or clinical programmes. The Fragment series was started in 2007 and continues with the theme, having over three-quarters of the presentations focused on case studies. The conference will include successful examples from all types of fragment-based approaches, including high concentration, NMR, SPR and X-ray screening ...

Search for Identifying A Library Member By Means Of A Tag, Label, Or Other Readable Or Detectable Entity Associated With The Library Member (e.g., Decoding Process, Etc.) Patents and Patent Applications (Class 506/4) Filed with the USPTO

The successful applicant have or will have a PhD degree in a subject relevant to our research, including Computational Biology (bioinformatics, systems biology), Computer Science, Statistics, Pharmacology, Chemistry (computational chemistry, medicinal chemistry) and Biology (structural biology, molecular and cell biology). At least one of the following conditions must be satisfied: 1) a strong background in software engineering and the ability to develop novel biofinformatic software/databases, 2) experience in handling large-scale biological data such as those from transcriptomic and proteomic experiments and 3) the ability to analyze small-molecule compounds and their targets using tools in chemoinformatics and computer-aided drug design.. A good balance of scientific and interpersonal skills will be essential and willingness to tackle interdisciplinary research questions is advantageous.. [Location] ...

Preliminary evaluations of large microbial libraries for potential producers of novel antimicrobial proteins require both qualitative and quantitative methods to screen for target enzymes prior to investing higher research effort and resources. hydrolytic activity of protein antimicrobials. The ability to label specific heat-killed cell tradition substrates with Remazol amazing blue R dye expands this capability to tailor the dye-release assay to characterize enzymatic activity of interest. 168 (American Type Tradition Collection; ATCC 23857). Incubate at 30 °C with shaking (125 rpm) until the tradition reaches an exponential phase of ABT-869 growth defined as a rapid growth phase resulting in the doubling of the bacterial culture. For the cultivation of subsp. (ATCC 10708) use nutrient broth as a growth medium at 37 °C with shaking (125 rpm). Heat-kill each culture by autoclaving for 10 min at 121 °C under 3 atm of pressure. Harvest ABT-869 the heat-killed bacterial substrate by ...

Audience Students and Faculty of the Gerstner Sloan Kettering Graduate School are invited to attend. FINAL EXAMINATION The public lecture will be followed by a defense of the thesis, at which attendance will be restricted to the Examining Committee and other interested members of the Faculty of the Gerstner Sloan Kettering Graduate School. Examining Committee