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Hegde S.S.,Theravance | Okusanya O.O.,Institute for Clinical Pharmacodynamics | Skinner R.,Theravance | Shaw J.-P.,Theravance | And 5 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2012

TD-1792 is a novel glycopeptide-cephalosporin heterodimer investigational antibiotic that displays potent bactericidal effects against clinically relevant Gram-positive organisms in vitro. The present studies evaluated the in vivo pharmacokinetics (PK) and pharmacodynamics (PD) of TD-1792 in the neutropenic murine thigh infection animal model. TD-1792, dosed subcutaneously (SC), produced dose-dependent reduction in the thigh bacterial burden of several organisms, including methicillin-susceptible and -resistant strains of Staphylococcus aureus and Staphylococcus epidermidis (MSSA, MRSA, MSSE, MRSE, respectively), penicillin-susceptible strains of Streptococcus pneumoniae (PSSP), Streptococcus pyogenes, and vancomycin-intermediate-susceptible Staphylococcus aureus (VISA). In single-dose efficacy studies, the 1-log 10 CFU kill effective dose (ED 1-log kill) estimates for TD-1792 ranged from 0.049 to 2.55 mg/kg of body weight administered SC, and the bacterial burden was reduced by up to 3 log 10 CFU/g from pretreatment values. Against S. aureus ATCC 33591 (MRSA), the total 24-h log 10 stasis dose (ED stasis) and ED 1-logkill doses for TD-1792 were 0.53 and 1.11 mg/kg/24 h, respectively, compared to 23.4 and 54.6 mg/kg/24 h for vancomycin, indicating that TD-1762 is 44-to 49-fold more potent than vancomycin. PK-PD analysis of data from single-dose and dose-fractionation studies for MRSA(ATCC 33591) demonstrated that the totaldrug 24-h area under the concentration-time curve-to-MIC ratio (AUC/MIC ratio) was the best predictor of efficacy (r 2=0.826) compared to total-drug maximum plasma concentration of drug-to-MIC ratio (Cmax/MIC ratio; r 2=0.715) and percent time that the total-drug plasma drug concentration remains above the MIC (%Time>MIC; r 2=0.749). The magnitudes of the total-drug AUC/MIC ratios associated with net bacterial stasis, a 1-log 10 CFU reduction from baseline and near maximal effect, were 21.1, 37.2, and 51.8, respectively. PK-PD targets based on such data represent useful inputs for analyses to support dose selection decisions for clinical studies of patients. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

Samara E.,PharmaPolaris International Inc. | Shaw J.-P.,Theravance | Shaw J.-P.,Bioduro Inc. | Barriere S.L.,Theravance | And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2012

A population pharmacokinetic model of telavancin, a lipoglycopeptide antibiotic, was developed and used to identify sources of interindividual variability. Data were obtained from healthy subjects (seven phase 1 studies), patients with complicated skin and skin structure infections (cSSSI; two phase 2 and two phase 3 studies), and patients with hospital-acquired pneumonia (HAP; two phase 3 studies). A two-compartment open model with zero-order input best fit the telavancin data from healthy individuals and patients with cSSSI or HAP. Telavancin clearance was highly correlated with renal function and, to a lesser extent, with body weight. Other covariates were related to at least one parameter in cSSSI (gender, bacterial eradication, and surgery) or HAP (age of≥75 years) but did not markedly affect exposure. These analyses support current dosing recommendations for telavancin based on patient weight and renal function. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

Jacob L.S.,University of Texas Southwestern Medical Center | Wu X.,University of Texas Southwestern Medical Center | Dodge M.E.,University of Texas Southwestern Medical Center | Fan C.-W.,University of Texas Southwestern Medical Center | And 7 more authors.
Science Signaling | Year: 2011

The Hedgehog (Hh) and Wnt signal transduction pathways are master regulators of embryogenesis and tissue renewal and represent anticancer therapeutic targets. Using genome-wide RNA interference screening in murine cultured cells, we established previously unknown associations between these signaling pathways and genes linked to developmental malformations, diseases of premature tissue degeneration, and cancer. We identified functions in both pathways for the multitasking kinase Stk11 (also known as Lkb1), a tumor suppressor implicated in lung and cervical cancers. We found that Stk11 loss resulted in disassembly of the primary cilium, a cellular organizing center for Hh pathway components, thus dampening Hh signaling. Loss of Stk11 also induced aberrant signaling through the Wnt pathway. Chemicals that targeted the Wnt acyltransferase Porcupine or that restored primary cilia length by inhibiting the tubulin deacetylase HDAC6 (histone deacetylase 6) countered deviant pathway activities driven by Stk11 loss. Our study demonstrates that Stk11 is a critical mediator in both the Hh and the Wnt pathways, and our approach provides a platform to support the development of targeted therapeutic strategies.

Tan J.-A.T.,Beckman Research Institute | Song J.,Beckman Research Institute | Song J.,Bioduro Inc. | Chen Y.,Beckman Research Institute | Durrin L.K.,Beckman Research Institute
Molecular and Cellular Biology | Year: 2010

Special AT-rich sequence-binding protein 1 (SATB1) is a tissue-restricted genome organizer that provides a key link between DNA loop organization, chromatin modification/remodeling, and transcription factor association at matrix attachment regions (MARs). The SUMO E3 ligase PIAS1 enhances SUMO conjugation to SATB1 lysine-744, and this modification regulates caspase-6 mediated cleavage of SATB1 at promyelocytic leukemia nuclear bodies (PML NBs). Since this regulated caspase cleavage occurs on only a subset of SATB1, and the products are relatively stable, proteolysis likely mediates cellular processes other than programmed cell death. However, the mechanism for the spatial and temporal regulation of SATB1 sumoylation and caspase cleavage is not known. Here we report that these processes are controlled by SATB1 phosphorylation; specifically, PIAS1 interaction with SATB1 is inhibited by phosphorylation. Mutagenesis studies identified interaction of the PIAS SAP (scaffold attachment factor-A/B/acinus/PIAS) motif with SATB1 N-terminal sequences. Notably, phosphorylation of SATB1 at threonine-188 regulates its interaction with PIAS1. Sequences near this phosphorylation site, LXXLL (residues 193 to 197), appear to be conserved among a subset of SUMO substrate proteins. Thus, this motif may be commonly involved in interaction with the PIAS SAP, and phosphorylation may similarly inhibit some of these substrates by preventing their interaction with the ligase. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Ding H.X.,PharmaPhase Co. | Leverett C.A.,Pfizer | Kyne R.E.,Pfizer | Liu K.K.-C.,Lilly China Research and Development Center | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2014

New drugs introduced to the market every year represent a privileged structure for a particular biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of twenty-six NCEs that were launched or approved worldwide in 2012 and two additional drugs which were launched at the end of 2011. © 2014 Elsevier Ltd. All rights reserved.

Van Aller G.S.,Glaxosmithkline | Carson J.D.,Glaxosmithkline | Tang W.,Bioduro Inc. | Peng H.,Bioduro Inc. | And 4 more authors.
Biochemical and Biophysical Research Communications | Year: 2011

The PI3K signaling pathway is activated in a broad spectrum of human cancers, either directly by genetic mutation or indirectly via activation of receptor tyrosine kinases or inactivation of the PTEN tumor suppressor. The key nodes of this pathway have emerged as important therapeutic targets for the treatment of cancer. In this study, we show that (-)-epigallocatechin-3-gallate (EGCG), a major component of green tea, is an ATP-competitive inhibitor of both phosphoinositide-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) with Ki values of 380 and 320. nM respectively. The potency of EGCG against PI3K and mTOR is within physiologically relevant concentrations. In addition, EGCG inhibits cell proliferation and AKT phosphorylation at Ser473 in MDA-MB-231 and A549 cells. Molecular docking studies show that EGCG binds well to the PI3K kinase domain active site, agreeing with the finding that EGCG competes for ATP binding. Our results suggest another important molecular mechanism for the anticancer activities of EGCG. © 2011 Elsevier Inc.

Drug discovery outsourcing - your guide to the commercial potential of services and companies in this market Where is the drug discovery outsourcing market heading? Visiongain's new report gives you revenue predictions for the drug discovery outsourcing market and its submarkets from 2015 to 2025, helping you stay ahead. Our new 223-page report provides 149 tables, charts, and graphs. Discover the growing trends of this industry. In particular, our new study lets you assess forecasted sales at overall world market and national level. You will see financial results, drivers and restraints, and revenue predictions. Besides revenue forecast to 2025, this report provides you with market shares, business outlooks, qualitative analyses (including SWOT and Porter's Five Forces Analysis), company profiles and commercial partnerships. Also, read the full transcript of three exclusive expert opinion interviews to inform you about prospects for investments and sales: - Dr. Mario Polywka, Chief Operating Officer, Evotec - Dr. John Davis, Director of Discovery & Dave Roberts, Business Development Director, Radiochemistry, Selcia - Dr. Paul Overton, Executive VP, Business Development & Marketing, Apuit See revenue forecasts for leading drug discovery outsourcing sectors Along with prediction of overall world market value to 2025, our report shows you revenue forecasting for the four services sectors at world level: • Chemistry services market forecast 2015-2025 • Biology services market forecast 2015-2025 • Lead optimisation market forecast 2015-2025 • Lead identification and screening market forecast 2015-2025 The analysis helps you identify market potential with individual revenue forecasts, annual growth rates and CAGRs and market shares. To see a report overview please email Sara Peerun on Discover prospects of the leading national markets for the drug discovery outsourcing The drug discovery outsourcing market is becoming increasingly global as companies look to lower costs by off-shoring their work to CROs based in emerging economies. You will discover individual revenue forecasts, annual growth rates, CAGRs, and market shares to 2025, as well as written supporting analyses for each of the 13 leading national markets and the rest of the world (RoW): • US • Japan • Germany • France • UK • Italy • Spain • China • Brazil • Russia • India • South Korea • Mexico • Rest of the World Demand for CROs based in emerging markets will be a major driver of growth in this market. Leading companies and potential for market growth Our new study predicts the world market for drug discovery outsourcing will reach $16.6bn in 2015. There is the increasing trend for pharmaceutical and biotech companies to form partnerships and alliances with CROs during the early drug discovery phase. Our research profiles leading companies, assessing their financial performance and products. You will see which organisations hold the greatest potential and what services each offer. See the profiles of 14 leading companies: • Albany Molecular Research (AMRI) • Aptuit • Charles River Laboratories (Acquired Galapagos CRO in 2014) • Covance (Acquired by LabCorp in 2015) • Cyprotex • Domainex • Evotec • GenScript • Pharmaceutical Product Development (PPD) • Quintiles • Selcia • Viva Biotech • WIL Research Laboratories • WuXi AppTec In general, a company profile gives you the following information: • Drug discovery revenue forecast from 2015 to 2025 • Historical and recent revenue figures • Description of services and products • Assessment of recent developments - mergers and acquisitions (M&A), collaborations, partnerships and alliances To see a report overview please email Sara Peerun on How the Drug Discovery Outsourcing Market Forecast 2015-2025: Opportunities for Leading Companies  report delivers In summary, our 223-page report gives you the following knowledge: • Revenue forecast to 2025 for the world drug discovery outsourcing market and 4 leading submarkets - Discover the industry's prospects, finding promising areas for investment and revenues. • Revenue forecasts to 2025 for the leading 13 national markets - US, Japan, Germany, France, UK, Italy, Spain, Brazil, Russia, China, India, South Korea, Mexico and the Rest of the World • Assessment of 14 leading companies - hear about collaborations, partnerships, contracts and alliances and predicted revenues to 2025 • Analysis of what stimulates and restrains that industry and market - assess challenges and strengths, helping you compete and get advantages. • View opinions from our survey, seeing interviews with leading drug discovery outsourcing experts. You will find quantitative and qualitative analyses with independent predictions. You will receive information that only our report contains, staying informed with this invaluable business intelligence. Information found nowhere else With our study you are less likely to fall behind in knowledge or miss opportunities. See how you could benefit your research, analyses, and decisions. Visiongain's study is for everybody needing commercial analyses for the drug discovery outsourcing market and leading CROs that offer these services. You find data, trends and predictions. Please order our report now. To request an exec summary of this report please email Sara Peerun at or call Tel: +44 (0) 20 7336 6100 AbbVie Actavis Acurian ADDC Advion Bioanalytical Labs Albany Molecular Research (AMRI) Alexion AMRI Apredica Aptuit Argenta Ark Therapeutics AstraZeneca Auspherix Bayer Behrman Capital Bio City BioDuro BioFocus BioPontis Alliance Boehringer Ingelheim Pharmaceuticals Bristol Myers Squibb C4X Discovery (C4XD) Cantab Caprion Proteomics Catalent Pharma Solutions ChanTest Charles River Laboratories CHDI Foundation ChemBridge ChemDiv Convergence Pharmaceuticals Covance LabCorp CRL CTSI Cyprotex Daiichi Sankyo Domainex Synthesis Med Chem Elan Eli Lilly Enamine Evotec Fidelity Growth Partners India (FGPI) Forma Therapeutics Fraunhofer Institute for Molecular Biology and Applied Ecology Galapagos GE Healthcare Genentech GenScript Great Lakes Chemical Corp GSK HD Biosciences Horizon Hypha Discovery ICON IMI Immatics Janssen Pharmaceuticals Johnson & Johnson Innovation KDDF Kellogg Company Knopp Biosciences LabCorp Laurus Labs Marshall University MedImmune Merck Midwest BioResearch MRC Technology NextCODE Health Ono Oxford Asymmetry International Parexel Pharmaceutical Product Development (PPD) Proteros Quintiles Ricerca Biosciences LLC Roche Rules-Based Medicines Sanofi Scynexis Europe Selcia ShangPharma Corporation Shire US Manufacturing Inc Siena Biotech SmithKline Beecham Tigermed Consulting UC San Francisco (UCSF) UCB Pharma Viva Biotech VivoPath WCCT Global WIL Research Laboratories WuXi AppTec X-Chem Other Organisations Mentioned in This Report ABO Academic Consortium: St George's, University of Manchester Academy of Military Medical Sciences Beijing Genomics Institute Biomedical Catalyst Fund Bundesverband Medizinischer Auftragsinstitute (BVMA) Cambridge University Dundee University Indiana Clinical and Translational Sciences Institute (CTSI) Innovative Medicine Initiative (IMI) JOINN Laboratories National Centre of Biomedical Analysis National Institute for Food and Drug Control North Carolina University PhRMA (Pharmaceutical Research and Manufacturers of America) The European CRO Federation (EUCROF) The Food and Drug Administration FDA (U.S) The Korea Drug Development Fund (KDDF) The Royal Society of Chemistry The Russian Corporation of Nanotechnologies The University of Edinburgh The University of Oxford The Wellcome Trust University of North Carolina US National Institutes of Health (NIH) To see a report overview please email Sara Peerun on or call Tel: +44 (0) 20 7336 6100.

News Article | September 25, 2013

Little information has been made public about Waltham, MA-based X-Chem since it started up in early 2010. But the startup has come up for air to give the type of announcement that every drug discovery company craves: a member of Big Pharma has snapped up a few drug candidates that its technology helped identify. X-Chem revealed two pieces of news on Tuesday: first, that it has been in a partnership with AstraZeneca (NYSE: AZN) since May 2012. It’s a two-year collaboration through which the pharma giant is leaning on X-Chem to find new small molecule drugs. But more importantly, that partnership has progressed to the point that AstraZeneca has licensed three potential drug programs coming from that discovery work: two directed at protein-protein interaction targets implicated in cancer and respiratory/inflammatory diseases, and one focused on an antibacterial target known to be difficult to make drug candidates against, according to X-Chem chief business officer Diala Ezzeddine. While X-Chem didn’t disclose the financial terms of the licenses—or the details of the AstraZeneca partnership overall— it’s a big step for X-Chem because it marks the first time an industry player has licensed potential drug programs coming from its discovery platform. “It validates the fact that we’re generating compounds with bona fide lead potential,” Ezzeddine says. “[T]hat is really the core of our business model, it’s what we’re looking to do for our partners.” X-Chem was formed in 2010 by co-founders Richard Wagner (its president and CEO), Gordon Binder (the former chairman and CEO of Amgen), and his son, Brant Binder. The company has raised just over $8.5 million to date, with most of that figure coming from an investment in 2010 from Pharmaceutical Product Development (PPD), the large contract research organization, Wagner says. The startup has 32 employees and certain additional consultants, and through the PPD partnership, also has the ability to tap chemists working for PPD subsidiary BioDuro. X-Chem isn’t disclosing how much cash it has in the bank, but it doesn’t need to raise additional funds for operations anytime soon, according to Wagner. Like many other companies in the crowded field of drug discovery, X-Chem is built around a technology that is supposed to help pharmaceutical companies and others screen for leads to potential drug candidates. It brings in cash through milestone payments and royalties should its partners pick up those lead compounds, and develop them into drugs. X-Chem’s platform is a comprised of a few different services: a proprietary library of small molecules, a combination of drug screening approaches—some generated in-house, and some that have been used by others—and chemical informatics tools and experts to look at the data and find the right molecules, according to Wagner. X-Chem is applying that approach to disease targets that are historically difficult to drug with small molecules, such as protein-protein interactions, epigenetic targets, antibacterial targets, or ubiquitin ligases. “For very difficult targets like this, you need an integrated suite of technologies to do it,” Wagner says. “It’s not a one-stop shop kind of thing, you need quite a bit of expertise around it.” X-Chem’s ability to prove that approach is different than the competition will come from both its ability to secure partnerships, and have those partnerships lead to real drugs. To this point, X-Chem has only made one partnership public: a deal with Roche in 2010 to help the pharma giant discover drugs. And while Ezzeddine says X-Chem “successfully” completed that partnership—it’s no longer ongoing—she wouldn’t specify how. Even so, X-Chem officials say they’ll soon be disclosing more about the work the company has been doing in stealth mode. Ezzeddine says that X-Chem has other similar partnerships in place with several large pharmaceutical companies, academic institutions, and biotechs—though, at least as of yet, she couldn’t reveal just who those deals are with. “We’re hoping we’ll be announcing more in the future.” Ezzeddine says.

News Article | November 8, 2016

SAN DIEGO, Nov. 8, 2016 /PRNewswire/ -- BioDuro, LLC, announced today the addition of an SPX Anhydro MicraSpray 150, to its suite of established GMP spray drying capabilities that include an SPX Anhydro MicraSpray 35 and Buchi B90 Nano in its San Diego facility. This expanded capacity...

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