Archive for May, 2010
Evotec OAI and Serono Sign Assay Development and Screening Services Agreement
Last Updated on Thursday, 20 May 2010 11:07 Written by Editor Thursday, 20 May 2010 11:07
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Leading the way
Last Updated on Friday, 14 May 2010 11:06 Written by Editor Friday, 14 May 2010 11:06
Successful drug research depends on high-quality hits in early screening. Trevor Perrior, research director at Domainex, explains why researchers are adopting a new method that turns high-throughput screening on its head
To some people, high-throughput screening (HTS) is synonymous with finding hits. But is it the best and only system? More and more drug researchers say they are looking for a faster and more cost-effective replacement. LeadBuilder was developed as an alternative to HTS that saves time and money because only compounds likely to become a drug are screened. HTS works the opposite way round – it ploughs through an enormous, random library of compounds and the hits are tested afterwards to find the most ‘drug-like’.
HTS is like searching for a needle in a vast haystack using a bulldozer. It is expensive because – paradoxically – the chance of finding the needle increases if you have more hay in which to look. Hundreds of thousands, or even millions, of compounds must be collected before HTS can begin. You also need to buy the bulldozer. Equipment like assay platforms and automated machinery must be purchased. HTS has high ongoing costs too, such as reagents, supplying proteins or cells, and replenishing the compound collection over time.
Once the equipment is running, screening seems very fast at first glance. Some estimates claim 10,000–100,000 compounds a day can pass through an HTS system. But preparing for HTS is an often forgotten time-sink. It takes time to establish a robust assay suitable for HTS and to obtain enough high-quality protein or cells to screen the whole compound collection.
Analysing HTS results is also time-consuming. Bulldozing your way randomly through any old compounds means hits often are not very ‘drug-like’. Hundreds of hits must be exhaustively tested for safety, bioavailability, novelty and affinity for the target.
A decade ago, it was less important that HTS was expensive and hard to set up. Big pharmaceutical companies with large budgets and laboratories did most drug discovery. Now, spin-off companies, small biotechs, research institutions and academic labs are increasingly getting in on the act. Many cannot afford to run an HTS operation in-house or pay perhaps £100,000–£250,000 to outsource a screen.
LeadBuilder turns HTS on its head. Instead of screening everything, the system physically screens only compounds that look like drugs or hits. Returning to our haystack idea, the system only picks short “needle-like†straws, making it easier to find the ones that really shine
Based on state-of-the-art virtual modelling and screening software, LeadBuilder has four main modules: LibraryBuilder, CompoundProfiler, ScreenBuilder and StructureBuilder
The system starts with CATS (Compounds Available To Screen). These are a set of commercially available compounds sourced from reliable suppliers stored in the LibraryBuilder module.
ranked by drug potential
CompoundProfiler finds NICE (Interesting Chemical Entities) CATS by calculating each CATS’ molecular properties and predicting its physiochemical, pharmacokinetic and toxicity profile
CATS are then ranked by how ‘drug-like’ they are. NICE CATS meet every criterion for the ‘perfect’ screening hit – they have excellent molecular properties, good ADME, low toxicity and interact well with a target protein.
Choosing NICE CATS involves creative thinking about what makes a ‘drug-like’ compound. For example, after reviewing 37 hit-to-lead programmes, we found that high ligand efficiency (binding energy per atom) predicted hits that were easy to optimise into drug candidates. Higher ligand efficiencies resulted from certain structural features like charged groups (e.g. N+). So Domainex developed an algorithm that predicts a ligand efficiency from a compound’s structural features. We use this to eliminate poorly performing CATS.
The next stage in building leads is ScreenBuilder – a virtual screening engine that works on NICE CATS. Using information about the target protein, any known ligands or both of these, this module can screen by a comÂbination of docking, pharmacophore searches and privileged fragment recognition. If the target protein is unknown, the system can identify a surrogate with a similar active siteThree real-life examples can illustrate how ScreenBuilder works: first, screening with pharmacophores derived from a known ligand, followed by docking into the x-ray structure of a protein; second, searching with ligand-based pharmacophores; and third, using only information about the target protein structure.
Example 1: Finding small molecules to inhibit protein-protein or peptide-peptide interactions is notoriously difficult. But LeadBuilder managed it. ScreenBuilder found 47 compounds that blocked a growth factor – natural peptide – from binding to its protein receptor. Aberrant growth factor signalling often drives tumour growth.
Domainex was given an x-ray structure of the ligand-binding pocket of the growth factor receptor with an oligopeptide fragment of the growth factor ligand bound to it. LeadBuilder analysed the ligand-binding pocket to define search criteria. Several structural features of the oligopeptide – H-bond donors and acceptors and a lipophilic group – seemed essential for binding to the receptor.
Next, the NICE database was virtually screened for compounds that contained these features and could be ‘docked’ into the protein’s active site. Domainex’s client lined up a subset of these compounds for further screening.
The project is currently in its hit-to-lead phase. Altogether, LeadBuilder identified 950 compounds for screening, delivering a 5% hit rate over several structural types. This made it 10 times more productive than another vendor’s focused library of 1000 compounds, which found only five hits (0.5% hit rate).
Example 2: A patent was filed on several compounds identified during another LeadBuilder project because they had commercially interesting activity levels. Domainex had been just given one known ligand to work with. The client was interested in compounds that would stimulate bone growth to accelerate the healing of fractures. It had developed a cell-based assay to look for compounds that switched on a signalling pathway that would cause deposition of bone. The ligand given to Domainex as a starting point was the only stimulator it had found for the pathway – it was keen to find others as potential drugs and for mechanism-of-action studies.
Domainex screened the NICE database using three pharmacophoric features based on the known ligand. Around 100 compounds were selected for screening, with the emphasis being on cellular penetration. During screening, our client found a hit with five times the activity of the known ligand. We are now helping it with a follow-up medicinal chemistry programme to find even better compounds.
Example 3: Protein kinases are important drug targets for a number of diseases. Many of the known inhibitors work by competing with the kinase substrate ATP. The problem with this approach is that it is difficult to find compounds that stop ATP binding to one kinase, but have no effect on the binding of ATP to other kinases. This selectivity problem means that kinase inhibitors often have side-effects caused by them blocking non-target kinase enzymes.
Our client wanted to find a selective inhibitor of a kinase that is a well-known cancer target, and had a novel hypothesis – did this protein kinase have a natural regulatory site that they could exploit with small-molecule drugs? The answer was yes. The client has patented the IP and is using it to secure funds. Domainex is now helping it develop a programme to turn its hits into leads.
An x-ray structure of the kinase showed that, in the naturally occurring inactive form, part of the enzyme ‘loops’ around to block the substrate protein binding site. On activation, this loop must move away to reveal a groove on the enzyme where the protein substrate can bind. An inhibitor that sits in this groove would stop catalysis by the kinase.
LeadBuilder found a four-point pharmaco-phore based on the key features of the “autoinhibitory loop†and an analysis of its binding groove on the surface of the enzyme (see Fig. 5). Using ScreenBuilder, potential ligands were selected from the NICE database using this pharmacophore and were docking into the hypothesised binding pocket.
Domainex recommended that the client screen 450 compounds based on this research. When tested against the kinase, this gave a 6% hit rate – 27 hits in four structural classes. Four of these showed promise in a follow-up cell-based screen.
In conclusion, dissatisfaction with HTS is growing. To many, finding hits seems like looking for a needle in a haystack. LeadBuilder is a smarter alternative. It may not yet offer pinpoint accuracy, but it can deliver ten times more hits during drug development.
source: manufacturingchemist.com
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Compound screening for drug development made simpler
Last Updated on Thursday, 13 May 2010 12:47 Written by Editor Thursday, 13 May 2010 12:47
The identification of compounds that could be promising candidates for drug development has become easier following research by the Walter and Eliza Hall Institute’s medicinal chemistry group.
Dr Jonathan Baell and Dr Georgina Holloway have developed a series of ‘filters’ that can be used to weed out those molecules likely to come up as false positives when screening a chemical library for compounds that could be useful in drug development.
High-throughput chemical screening (HTCS) seeks to identify chemical compounds that interact with a target protein and are therefore potential candidates for drug development. There can be from 30,000 to one million compounds in a screening library and thousands of compounds may be flagged as ‘positive’ for interaction with a protein of interest. These compounds then become the subject of time-consuming medicinal chemistry as scientists seek to refine them for entry into the drug development pipeline.
Dr Baell said about 10 per cent of compounds in any commercially available screening library might show up as false positives, potentially wasting hundreds of hours of scientists’ time as they undertake labour-intensive medicinal chemistry to optimise these molecules.
“We’re trying to remove molecules from the screening process that trick scientists into thinking they could be useful for being developed into drugs to treat disease but instead become a dead end,” Dr Baell said.
To this end, Dr Baell and Dr Holloway analysed data from previous chemical screens and developed a way of clearly identifying those molecules likely to show up as false positives.
“These pan assay interference compounds, or PAINS as I like to call them, caused us some grief not so many years ago. For that reason, Georgina and I have taken some effort to identify these PAINS.”
Dr Baell has made it possible for others to identify these troublesome molecules by developing ‘filters’, text files that can be incorporated into the software used to screen chemical libraries.
The filters were made publically available on 4 February through online publication in the Journal of Medicinal Chemistry.
High-throughput chemical screening has been used by large pharmaceutical companies for more than 20 years. In the past decade scientists at universities and research institutes and in small biotechnology companies have had increasing access to HTCS. “Many of them have spent vast amounts of time and money optimising and patenting molecules that were never going to amount to anything,” Dr Baell said.
“We were in a position where we had all the data, we had the software, and we had the expertise to identify these molecules. Importantly, we also had the ability to publish our data.
“Pharmaceutical companies, which have used high-throughput chemical screening for many years, would know about many compounds that turn up as false positives. But they also operate in a competitive environment where publishing this data could compromise their competitive edge. For this particular situation, we didn’t have such constraints.”
Dr Baell said that within 48 hours of publishing the filters he was contacted by a number of pharmaceutical companies wishing to use them to assess their impact on their own high throughput screening libraries.”
source: eurekalert.org
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Evotec Gains Access to Hypha’s MycoDiverse Natural Products Library
Last Updated on Thursday, 13 May 2010 12:43 Written by Editor Thursday, 13 May 2010 12:43
Evotec negotiated access to U.K.-based Hypha Discovery’s MycoDiverse™ fungi-derived natural product screening library. The deal means Evotec will be able to offer the library to clients through its hit and lead identification services.
Hypha currently has access to over 2,500 strains of higher basidiomycete and ascomycete fungi, many from South American and South East Asian rainforests. The firm’s MycoDiverse library comprises low-molecular weight compounds derived from temperate and tropical basidiomycete fungi (mushrooms and toadstools).
The library is generated using a proprietary fermentation technology that uses stimulators and growth media to reproduce stress of life for rainforest fungi. Hypha claims this promotes the production of biologically active molecules with unusually high chemical novelty.
“We see access to Hypha’s high-quality natural product collection as a logical step towards offering our customers further choices for lead identification,†comments Mark Ashton, Ph.D., Evotec’s evp business development.
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High Throughput Screening 2010 Study Finds HTS Laboratories Using Effective Screening Strategies and Innovative Technologies to Increase Drug Discovery Success
Last Updated on Thursday, 13 May 2010 11:31 Written by Editor Thursday, 13 May 2010 11:31
HTS laboratories are essential contributors to drug discovery, participating extensively in assay development and lead optimization as well as in primary and secondary screening of compound libraries. Effective screening strategies adopted by HTS laboratories include the use of more complex biological systems: more membrane-bound targets, more cell-based high content assays, and increased use of stem cells and primary cells.Fifty-two directors from HTS laboratories and thirty-three executives from suppliers of HTS products and services in Asia, Europe and North America were extensively interviewed in a recently published study, High Throughput Screening 2010: Effective Strategies, Innovative Technologies, and Use of Better Assays, described technology and strategies that are evolving to increase success in drug discovery.
HTS laboratories are exploring novel targets and strategically expanding compound libraries to include more diverse backbones, more target-focused compounds, natural products, and biologics. The directors at HTS laboratories also plan to employ improved technologies, including further adoption of HCS and label-free technologies and more accurate liquid handling dispensers.
HTS laboratories funded through NIH or other private foundations have an increased presence, as more universities and institutes initiate translational research. This new report includes analysis and data from interviews with HTS laboratory directors at these centers to better understand their impact on the high throughput screening market.
William Downey, President of HighTech Business Decisions, explains, “High throughput screening is established as a critical activity in drug discovery. In the past two years, challenging targets have yielded to advances in assay and detection technologies. High content and label-free assays and new interest in stem cells as promising disease models are leading the way to improved drug discovery.â€
The findings and analysis are in this 1050–page industry report, with over 300 charts and tables, High Throughput Screening 2010: Effective Strategies, Innovative Technologies, and Use of Better Assays. This new study was published in February 2010, and it is available from HighTech Business Decisions.
About HighTech Business Decisions
HighTech Business Decisions is a market research and consulting firm specializing in the areas of pharmaceutical drug discovery and biopharmaceutical contract manufacturing. The company has been producing in-depth public reports and customized benchmarking, market analysis and customer loyalty programs for over ten years. Visit us at www.hightechdecisions.com
source: businesswire.com
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Collaboration with GSK for Inflammatory Diseases
Last Updated on Thursday, 13 May 2010 11:23 Written by Editor Thursday, 13 May 2010 11:23
Cellzome inked a drug discovery alliance with GlaxoSmithKline in the field of inflammatory disease with a €33 million (about $44.79 million) up-front payment. The deal represents the companies’ second drug discovery partnership and will focus on exploiting Cellzome’s Episphere™ technology for the identification of small molecule candidates against targets from four different epigenetic classes.
The firms will work together to identify candidates, after which point GSK will take over all preclinical and clinical development as well as commercialization. It says if all programs under the alliance are successfully developed and commercialized, additional milestone payments could exceed €475 million, or almost $645 million. Cellzome’s E33 million up-front payment includes technology access fees and the purchase of equity.
Cellzome and GSK signed their first inflammatory disease collaboration in September 2008. Through this partnership the companies aim to identify and develop selective kinase inhibitors using Cellzome’s Kinobeads™ technology. In September 2009, Cellzome reported that the collaboration had achieved its fourth milestone.
Cellzome describes its Episphere platform as a suite of quantitative proteomics technologies that allows epigenetic targets to be screened in their native environment as part of their protein complexes, without the need for recombinant protein or any other artificial labeling. The technology is designed to allow measurement of the interaction of drugs with epigenetic targets directly in cells and tissues as well as distinguish between complexes in which epigenetic targets operate and monitor the effects of a drug on an epigenetic signature.
Cellzome‘s Kinobeads technology has been designed to quantitatively measure the extent that compounds or drugs interact with kinases within cells and tissues. The kinase-binding matrix can be used to measure the potency of compounds for about 300 different kinases and is sensitive enough to fingerprint compounds in terms of their kinase interactions, the company maintains. The Kinobeads technology underpins Cellzome’s target and biomarker discovery, screening, and selectivity profiling activities.
source: genengnews.com
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Evotec Signs High Throughput Screening Agreement With Active Biotech
Last Updated on Thursday, 13 May 2010 11:06 Written by Editor Thursday, 13 May 2010 11:06
Evotec AG (Frankfurt:EVT) (TecDAX) today announced that it has entered into a collaboration with Active Biotech AB (Stockholm:ACTI) to identify small molecule modulators of a priority biological target, selected by Active Biotech, involved in immune disorders and cancer.
Evotec will use its expertise and technologies in assay development, high throughput screening (HTS) and surface plasmon resonance (SPR) screening for the identification and validation of novel hits. In order to maximise the probability of finding high quality medicinal chemistry starting points, Evotec will screen its Lead Discovery Library, a small molecule collection designed for diversity, novelty and quality.
Dorthe da Graça Thrige, Director of Development of Active Biotech, commented: “We have a high regard for Evotec’s expertise and capabilities in assay development and compound screening. In addition, we are impressed with the excellent quality of Evotec’s Lead Discovery Library, which we believe will enable us to generate high quality hits, ensuring a smooth transition to medicinal chemistry activities. Importantly, the hits identified in the HTS will complement the ongoing lead optimisation of compounds identified in-house.”
Dr. Mark Ashton, Executive Vice President, Business Development of Evotec stated: “We are proud to have been selected by Active Biotech, a leading biotechnology company with advanced drug candidates in the area of immune modulation, to carry out hit identification activities on this important biological target. We look forward to supporting them in their quest to find novel treatments to address immune disorders and cancer.”
Evotec has a unique assay development and screening platform built around proprietary and the latest commercial technologies providing a flexible and high quality approach to lead identification. Evotec has successfully developed assays and high throughput screens for all of the major target classes including GPCR’s, kinases and other enzymes, ion channel and protein::protein interactions.
No financial details are disclosed.
About Evotec AG
Evotec is a leader in the discovery and development of novel small molecule drugs with operational sites in Europe and Asia. The Company has built substantial drug discovery expertise and an industrialised platform that can drive new innovative small molecule compounds into the clinic. In addition, Evotec has built a deep internal knowledge base in the treatment of diseases related to neuroscience, pain, and inflammation. Leveraging these skills and expertise the Company intends to develop best-in-class differentiated therapeutics and deliver superior science-driven discovery alliances with pharmaceutical and biotechnology companies. Evotec has long-term discovery alliances with partners including Boehringer Ingelheim, CHDI, Novartis, Ono Pharmaceutical and Roche. Evotec has product candidates in clinical development and a series of preclinical compounds and development partnerships, including for example a strategic alliance with Roche for the EVT 100 compound family, subtype selective NMDA receptor antagonists for use in treatment-resistant depression. For additional information please go to www.evotec.com.
About Active Biotech AB
Active Biotech AB (Stockholm:ACTI) is a biotechnology company with focus on autoimmune/inflammatory diseases and cancer. Projects in pivotal phase are laquinimod, an orally administered small molecule with unique immunomodulatory properties for the treatment of multiple sclerosis, as well as ANYARA for use in cancer targeted therapy, primarily of renal cancer. Further key projects in clinical development comprise the three orally administered compounds TASQ for prostate cancer, 57-57 for SLE and RhuDexTM for RA. Please visit www.activebiotech.com for more information.
Forward-looking statements
Information set forth in this press release contains forward-looking statements, which involve a number of risks and uncertainties. Such forward-looking statements include, but are not limited to, statements about our expectations and assumptions concerning our strategic collaborations, our regulatory, clinical and business strategies, the progress of our clinical development programmes and management’s plans, objectives and strategies. These statements are neither promises nor guarantees, but are subject to a variety of risks and uncertainties, many of which are beyond our control, and which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, the risks and uncertainties include, among other things: risks that product candidates may fail in the clinic or may not be successfully marketed or manufactured; the risk that we will not achieve the anticipated benefits of our collaborations, partnerships and acquisitions in the timeframes expected, or at all; risks relating to our ability to advance the development of product candidates currently in the pipeline or in clinical trials; our inability to further identify, develop and achieve commercial success for new products and technologies; the risk that competing products may be more successful; our inability to interest potential partners in our technologies and products; our inability to achieve commercial success for our products and technologies; our inability to protect our intellectual property and the cost of enforcing or defending our intellectual property rights; our failure to comply with regulations relating to our products and product candidates, including FDA requirements; the risk that the FDA may interpret the results of our studies differently than we have; the risk that clinical trials may not result in marketable products; the risk that we may be unable to successfully secure regulatory approval of and market our drug candidates; and risks of new, changing and competitive technologies and regulations in the U.S. and internationally.
The list of risks above is not exhaustive. Our most recent Annual Report on Form 20-F, filed with the Securities and Exchange Commission, and other documents filed with, or furnished to the Securities and Exchange Commission, contain additional factors that could impact our businesses and financial performance. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any such statements to reflect any change in our expectations or any change in events, conditions or circumstances on which any such statement is based.
This news release was distributed by GlobeNewswire, www.globenewswire.com
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SGX Pharmaceuticals Announces Strategic Collaboration To Develop And Commercialize BCR-ABL Inhibitor
Last Updated on Thursday, 13 May 2010 10:22 Written by Editor Thursday, 13 May 2010 10:22
Under the terms of the agreement, SGX will receive from Novartis $25 million in upfront payments and the purchase of SGX common stock. Along with success-based milestones, but excluding royalties, total payments to SGX could exceed $515 million, including a minimum of two years of research funding.
The success of Gleevec(TM) (imatinib), the first targeted therapy in Philadelphia Positive (Ph+CML) proven to inhibit BCR-ABL, has fundamentally changed the treatment of Ph+CML. However, a subset of patients develops resistance to Gleevec or cannot tolerate therapy. For these patients there are currently no other approved treatment options. Drug candidates from SGX’s lead series, developed from its FAST(TM) proprietary drug discovery platform, have exhibited activity against wild-type and drug resistant BCR-ABL mutants, including the most challenging T315I mutant.
“Novartis is the leader in developing novel targeted therapies to treat CML,†said Mike Grey, president and chief executive officer of SGX Pharmaceuticals. “With their extensive experience developing and commercializing Gleevec as well as development of the novel investigational compound, nilotinib/AMN107, we believe they are the ideal partner with whom to develop our series of next-generation BCR-ABL inhibitors. This is a tremendous validation of our FAST technology for generation of novel lead molecules for key therapeutic targets.â€
Background on the Agreement
SGX will be responsible for completing preclinical development of the lead candidate and submitting an Investigational New Drug application with the Food and Drug Administration. SGX will also be responsible for the completion of an initial phase I clinical study, after which time Novartis will be responsible for conducting further clinical development and commercialization of the compound.
In addition to the upfront and milestone payments, SGX will receive royalty payments upon successful commercialization of products developed under the collaboration. SGX retains an option to co-commercialize, in the U.S., oncology products developed under the agreement. If exercised, the option would enable SGX to reinforce the commercial presence in the North American hematology markets which the company plans to establish with the potential launch of Troxatyl(TM) in the second half of 2007, assuming the successful completion of the ongoing Phase II/III clinical trial for the treatment of third-line acute myelogenous leukemia and regulatory approval of Troxatyl for this initial indication in 2007.
Background on CML: Prognosis and Treatments
Chronic myelogenous leukemia is a malignant cancer of the bone marrow causing rapid and abnormal growth of white blood cells. According to the National Institutes of Health, approximately 4,600 new cases of CML are diagnosed annually, accounting for 7 to 20 percent of leukemia cases. CML is associated with a chromosome abnormality called the Philadelphia chromosome. Since its approval in 2001, Gleevec has become the standard of care for Ph+ CML. Results from the IRIS study (International Randomized Interferon versus STI571), the largest clinical trial to date for newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase, show that 90.3 percent of patients who were initially randomized to take Gleevec were still alive after 54 months.
The prevalence of CML has increased substantially because Gleevec therapy makes it possible for patients with CML to live with the disease much longer than possible with previously used treatments. Gleevec works directly on leukemic cells by inhibiting the action of BCR-ABL tyrosine kinase, the enzyme responsible for uncontrolled growth of leukemic cells. Despite this clinical success, resistance to Gleevec has emerged in a subset of patients. Once patients lose response to optimized doses of Gleevec, the only currently approved treatment is bone marrow transplantation preceded by high-dose chemotherapy and radiation, for which many CML patients are not eligible.
“We believe that a BCR-ABL inhibitor developed through this collaboration could have the potential to be used both as a monotherapy in second-line treatment of refractory or relapsed CML, and in combination with Gleevec or another agent in first-line treatment of CML,†added Dr. Stephen Burley, chief scientific officer of SGX Pharmaceuticals.
About: FAST, short for Fragments of Active Structures, is SGX’s proprietary fragment-based drug discovery platform for rapid identification of novel, potent and selective small molecule inhibitors of drug targets. FAST addresses many of the limitations of traditional approaches utilized by large pharmaceutical companies to find lead compounds, making it an attractive technology for targets that have not yielded promising leads from high-throughput screening.
FAST is based on a proprietary fragment library of approximately 1,000 structurally diverse, low molecular weight compounds. FAST integrates a series of technologies, including:
* A high-throughput capability to generate many different crystal structures of a target protein in parallel;
* The evaluation of the library of fragments and direct visualization of bound fragments utilizing X-ray crystallography; and
* The use of novel computational and structure-based design methods and iterative synthetic chemistry to optimize these fragments into drug candidates.
SGX believes these combined technologies generate an efficient platform for drug discovery that delivers lead compounds active against a wide range of targets, while accessing high chemical diversity and the potential for good drug-like properties.
About: SGX Pharmaceuticals is a biotechnology company focused on the discovery, development and commercialization of innovative cancer therapeutics. The Company’s lead product candidate, Troxatyl(TM), is currently being evaluated in a pivotal phase II/III trial for the treatment of third-line acute myelogenous leukemia, an indication for which there is currently no approved therapy or standard of care. SGX has developed a pipeline of oncology drug candidates based on its enabling, proprietary FAST(TM) drug discovery platform, including a portfolio of next generation BCR-ABL inhibitors. FAST allows for the rapid identification of novel, potent and selective small molecule compounds for well validated but challenging targets.
source: biotechconnection.com
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Thermo Fisher Scientific Showcases its Commitment to Innovation at Pittcon 2010
Last Updated on Thursday, 13 May 2010 10:20 Written by Editor Thursday, 13 May 2010 10:20
Thermo Fisher Scientific Inc. /quotes/comstock/13*!tmo/quotes/nls/tmo (TMO 54.80, -0.05, -0.08%) , the world leader in serving science, strengthens its position as the industry’s innovation powerhouse with a comprehensive showing of new high-end analytical instruments, laboratory equipment, software, consumables and reagents at Pittcon 2010, being held from February 28 – March 5 in Orlando. Whether providing customers with the ability to perform complex proteomics research, bringing industry-leading technologies to routine applications, or enabling fast and accurate analysis in the field, Thermo Fisher is committed to connecting customers with the tools, knowledge and insight to serve science in ways no other company can.”We are in the unique position of not only helping our customers to improve the quality of research, but also driving their productivity through improved workflows and operating processes,” said Marc N. Casper, president and chief executive officer of Thermo Fisher Scientific. “Our Thermo Scientific brand is accelerating their progress by providing industry-leading technologies, while our Fisher Scientific channel continues to streamline laboratory supply chain management for our customers.”
Thermo Fisher’s new technologies, products and services are highlighted this year in booths 2757 and 2657. Progress Starts Here is the theme reinforced through the company’s Thermo Scientific technology and innovation brand, while the Fisher Scientific brand represents choice and convenience through One Source, Infinite Solutions.
Enabling researchers to solve tomorrow’s challenges
As researchers close in on their understanding of disease, its causes and potential treatments, the speed and accuracy with which decisions are made becomes more critical to the process. For the proteomic researcher, for example, who is pushing the boundaries of science to discover new drugs, Thermo Fisher has reinvented ion trap technology with its new Thermo Scientific LTQ Velos platform. The improvements in speed and sensitivity in the LTQ Velos(TM) enable more confident sequence assignment and post-translational modification (PTM) identification.
The LTQ Orbitrap(TM) Velos(TM) combines the increased sensitivity and improved cycle time of the LTQ Velos with the proven mass accuracy and ultra-high resolution of the company’s revolutionary Orbitrap mass analyzer to deliver high-performance hybrid mass spectrometry.
Steven Gygi, PhD, Associate Professor of Cell Biology at Harvard Medical School has already witnessed the transformation this new technology has made possible for cellular proteome analysis. “The ability to analyze more samples in a day than we previously could in weeks — and with the assurance that the results are even more accurate — changes the rules of the game,” Gygi said.
The LTQ Orbitrap Velos mass spectrometer is capable of providing more analytical detail and specificity than ever before. Thermo Fisher’s leading mass spectrometry platform continues to evolve to satisfy the increasing demands of researchers who need to identify more proteins with increased sequence coverage and higher confidence, yet do so in less time.
The company is also meeting the demand for rapid screening and analysis of complex samples containing pesticides, metabolites or other target compounds by combining its highly effective Exactive(TM) benchtop liquid chromatography/mass spectrometry (LC/MS) system with its Transcend(TM) online sample extraction technology for a complete Thermo Scientific LC/MS solution. The TurboFlow(TM) technology in Transcend permits direct injection of complex matrices, virtually eliminating upfront sample preparation and delivering reliable analysis in a fraction of the time.
Industry-leading technologies for routine applications
This same focus on performance extends to a line-up of new Thermo Scientific chromatography instruments and consumables that are designed for routine analytical testing in applications such as food safety and environmental analysis, where accuracy, robustness and lifecycle costs are critical to customers. The new TSQ Quantum(TM) XLS gas chromatography-mass spectrometry (GC-MS) system features the innovative DuraBrite(TM) IRIS high-sensitivity ion source to offer better sensitivity for quantitative GC triple quadrupole analyses. When combined with the new TraceGOLD columns, the instrument delivers outstanding analytical performance.
The new Thermo Scientific Accela 1250 quaternary pump dramatically improves separation for complex mixtures, such as red wine, for dramatically improved speed and accuracy during ultra-high pressure liquid chromatography (U-HPLC) analysis. The Accela 1250(TM) features Force Feedback Control (FFC) and sets a new standard by eliminating the need for pulse dampening while maximizing flow accuracy and gradient precision under extreme operating conditions.
To measure chemical samples faster and with more confidence, Thermo Fisher provides two new additions to its molecular spectroscopy portfolio. The Thermo Scientific Evolution Array UV-Visible (UV-Vis) spectrophotometer uses advanced photodiode array (PDA) technology to provide simultaneous detection of all wavelengths throughout the ultraviolet and visible regions of the spectrum. The Thermo Scientific Lumina fluorescence spectrometer offers twice the resolution power of competitive instruments while increased sensitivity provides lower detection limits. Thermo Fisher delivers a new level of clarity in fluorescence measurement by reducing noise and providing more consistent baseline analysis.
The new Thermo Scientific benchtop photometric analyzer, Gallery(TM), addresses a wide range of routine applications, including quality control, food and beverage analysis, and water and environmental testing. The conveniently sized instrument is fully automated to accelerate analysis and improve performance for colorimetric, enzymatic and electrochemical measurements.
Driving laboratory and enterprise productivity
For 2010, the company is announcing a significant innovation in its suite of laboratory information management systems (LIMS) software. The new Web-based Thermo Scientific LIMS-on-Demand(TM) offers flexibility and ease-of-use, helping organizations replace inefficient, error-prone manual processes with an automated data management solution. Customers can create workflows, map sample lifecycles and generate automatic updates from any standard Internet connection while providing users with rapid access to up-to-the-minute data and information.
According to Vance Lemmon, PhD, University of Miami, the Miami Project to Cure Paralysis, “Our research requires attention to detail, documenting what we do, and using our funds and resources as effectively as possible. The ability to use a fully functional LIMS-on-demand through a secure Internet portal from any of our computers relieves our team of the burden of maintaining the LIMS and makes access to the LIMS much easier. As a result, we will be able to focus on our mission of discovering genes and drugs that can help promote regeneration.”
LIMS-on-Demand access provides a more flexible alternative to conventional LIMS so organizations can more easily and cost-effectively realize the benefits of improved technology at a pace that is consistent with their needs. For the cost of a monthly subscription fee, a laboratory can easily, affordably and securely access a fully functional, validated solution through a standard Web browser.
Thermo Fisher Scientific also provides a complete line of Thermo Scientific laboratory workstations, fume hoods, and accessories that improve laboratory efficiency and safety. New Hamilton(TM) Infinity(TM) and Hamilton(TM) Advantage(TM) fume hoods are highly ergonomic, with advanced safety and energy-saving features that make them ideal for virtually any laboratory. Both models feature “directed air technology” to enhance fume hood performance. The Infinity series features GreenFumeHood(TM) technology to essentially eliminate atmospheric pollution from the exhaust, minimizing associated building infrastructure and dramatically reducing energy consumption.
Fast and Accurate Analysis in the Field
Laboratory-quality elemental analysis in a handheld instrument is the hallmark of the Thermo Scientific Niton analyzer portfolio. The new Niton(TM) XL2 series continues the tradition of providing the industry’s most capable handheld X-ray fluorescence (XRF) analyzers designed for taking measurements anywhere and at any time, with accurate results available in seconds. XRF technology has been used extensively to identify sources of lead at ports and borders and is increasingly being used to identify toxic elements, including cadmium, in a variety of consumer products such as toys and jewelry.
Thermo Fisher Scientific recently completed the acquisition of a leading provider of handheld chemical analyzers, Ahura Scientific, expanding the Thermo Scientific portfolio of handheld analyzers to include non-destructive, field-based identification of solid and liquid chemicals. Using Fourier transform-infrared (FT-IR) and Raman spectroscopy technologies in a portable, rugged and easy-to-use form, these chemical and explosives identification products are deployed worldwide by U.S. and foreign military organizations, national and regional law enforcement agencies, hazmat teams and pharmaceutical companies.
The company has also expanded its range of water analysis instruments. Among the new products available is the Thermo Scientific Orion RDO BOD STAR bench meter and probe for EPA-approved, stir-free, optical dissolved oxygen measurements. Thermo Scientific Orion products are recognized worldwide for quality and accuracy, serving markets such as environmental, food and beverage, pharmaceutical and general laboratory equipment.
The Pittcon 2010 press conference will be Webcast live beginning at 12:00 pm on Monday, March 1, at www.thermofisher.com.
For access to all Thermo Fisher Scientific news and product photos related to Pittcon 2010, please visit the online media room at www.thermofisher.com/pittcon10.
About Thermo Fisher Scientific
Thermo Fisher Scientific Inc. /quotes/comstock/13*!tmo/quotes/nls/tmo (TMO 54.80, -0.05, -0.08%) is the world leader in serving science. Our mission is to enable our customers to make the world healthier, cleaner and safer. With revenues of more than $10 billion, we have approximately 35,000 employees and serve customers within pharmaceutical and biotech companies, hospitals and clinical diagnostic labs, universities, research institutions and government agencies, as well as in environmental and process control industries. We create value for our key stakeholders through two premier brands, Thermo Scientific and Fisher Scientific, which offer a unique combination of continuous technology development and the most convenient purchasing options. Our products and services help accelerate the pace of scientific discovery, and solve analytical challenges ranging from complex research to routine testing to field applications. Visit www.thermofisher.com.
SOURCE: Thermo Fisher Scientific Inc.
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US launches new regulatory science programm
Last Updated on Thursday, 13 May 2010 10:05 Written by Editor Thursday, 13 May 2010 10:05
Two major US government agencies have partnered to create a new regulatory science programme to ensure better integration between cutting edge science and regulatory processes in assessing new medical products or compounds flowing from biomedical research.
Announced on 24 February, the effort is a joint venture of the US National Institutes of Health (NIH) and the Food and Drug Administration (FDA), who will create a joint ‘Leadership Council’ to spearhead the collaborative work. The new body will be charged with ensuring that regulatory considerations form an ‘integral component of biomedical research planning’, and that ‘the latest science is integrated into the regulatory review process’, according to the two agencies.
Under the new endeavour, the NIH and FDA are also making a total of $6.75 million (£4.45 million) available over three years for work that can yield new methods, models or technologies that will provide better approaches to evaluating safety and efficacy in medical product development. The lion’s share of the money – $6 million – will come from the NIH.
‘Scientific advances will reduce the need for large animal studies to predict how humans will respond to chemical exposure,’ FDA spokesperson Karen Riley tells Chemistry World. ‘Some assessments will be able to be done using cell culture or genomic microarrays, which might be done more quickly and at lower cost.’
Among a range of activities, the agencies want to support work involving the implementation of assessment tools for emerging fields like nanomedicine and RNA interference therapy, and also support the development of novel manufacturing technologies to enhance product safety.
‘Weak and under-developed’Â
‘We have allowed the arm of regulatory science to become weak and under-developed,’ FDA commissioner, Margaret Hamburg, said during a 24 February briefing. If this ‘imbalance’ persists, she cautioned, the full potential of the biomedical research revolution will not be realised.
The American Chemistry Council (ACC) – an industry trade association for US chemical companies – supports harnessing new advanced molecular screening methods, but warns that many are premature.
‘Although these methodologies hold great promise, many aren’t yet ready for regulatory use,’ Rick Becker, an ACC senior toxicologist, tells Chemistry World.
Becker says additional research is needed to ‘develop confidence’ in these molecular screening techniques. ‘At some point, we believe data can be used to augment existing regulatory science and perhaps in the future replace existing animal testing in product safety assessment,’ he states.
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Institutional Profile: Sanford-Burnham Sets Up Shop in Florida
Last Updated on Saturday, 24 July 2010 04:09 Written by Editor Thursday, 13 May 2010 10:04
The Sanford-Burnham Medical Research Institute, headquartered in La Jolla, CA, dedicated its new Lake Nona campus in Orlando, FL, last fall. The $85 million building, which opened in April 2009, will employ more than 300 people. Florida attracted Sanford-Burnham in 2006 by offering a $350 million incentive package that included land, construction funds, and in-kind services.
The Lake Nona facility is part of a medical park that includes the University of Central Florida College of Medicine, Nemours Children’s Hospital, and M.D. Anderson Cancer Center-Orlando.
Researchers at Lake Nona will continue to carry out cutting-edge research that will complement areas established at Sanford-Burnham in La Jolla—cancer, infectious and inflammatory disease, aging and stem cells, and neuroscience. In addition, Lake Nona houses a new center for diabetes and obesity research that will cover cardiovascular disease, as well.
Chemical Biology Theme
A strong emphasis on chemical biology underlies all research areas and drives investigations. Chemical biology focuses on identifying small molecules that modulate disease pathways. “That theme weaves itself throughout our research and gets us closer to discoveries that are relevant to small molecule drug discovery,†says John Reed, M.D., Ph.D., president and CEO of Sanford-Burnham.
Finding the correct small molecule can advance a program to prototype medicines and clinical trials. Sanford-Burnham is one of only a few academic centers in the U.S. with advanced high-throughput screening (HTS) systems and access to a large chemical libraries approaching one million small molecules.
Sanford-Burnham’s small molecule drug discovery program is embodied within the Conrad Prebys Center for Chemical Genomics (CPCCG), an effort that involves 75 scientists working on both coasts. The development of HTS assays takes place in La Jolla, while Lake Nona specializes in HTS and houses an ultra-HTS robotic screening center.
The CPCCG provides a one-stop shop whose services span a range of biochemical and cell-based screens to find chemical hits and optimize them into biological probes or potential drugs. The equipment includes a first-in-class, highly flexible HighRes Biosolutions 3-POD nonagon ultra-HTS system and two PerkinElmer Janus workstations. “The robot can run more than one million assays in a workday at Lake Nona,†explains Dr. Reed.
Collaborators Wanted
The newly installed system is capable of handling 50 HTS campaigns a year, yet is currently operating below capacity. This makes Sanford-Burnham an ideal partner for pharmaceutical companies seeking to externalize R&D projects. “We’re looking for corporate partners that fit into our therapeutic research areas,†says Dr. Reed. Collaborations with Sanford-Burnham could identify innovative drug candidates to strengthen pharmaceutical pipelines. Two new partners are Johnson & Johnson Pharmaceutical Research and Development (J&JPRD) and Magellan Bioscience.
Sanford-Burnham will provide J&JPRD with access to HTS assay technologies to investigate drug targets for inflammatory diseases. The collaboration started in January 2009 and is Sanford-Burnham’s first broad-based partnership with a large pharmaceutical company.
Magellan Bioscience began collaborating with Sanford-Burnham in July 2009. The multidisciplinary drug discovery program identifies and develops novel marine microbial compounds that show potential as tools for biological research or new medicines. Marine microbes and their natural products provide a new source of drug candidates for the pharmaceutical industry.
Sanford-Burnham also offers NMR-based screening against targets for which no assay has been developed. “This is unusual in a nonprofit environment, and it’s one of our fortes,†adds Dr. Reed.
The NMR facility at Sanford-Burnham is the largest of its type affiliated with a nonprofit research institution, according to Dr. Reed. Sanford-Burnham’s NMR center includes four fully dedicated high-field magnets with automated sample changers, a library with 4,000 chemical fragments, and three-dimensional (3-D) modeling programs to evaluate hits. Other tools include robotic x-ray crystallography to investigate crystal structures of compounds and their binding to targets and high-content screening microscopy that performs HT phenotype screening.
Engineers at Sanford-Burnham are advancing the field of HT microscopy by developing software for automated image analysis and 3-D imaging systems to monitor cells growing in 3-D conformations in culture.
No Culture Gap
Pharmaceutical firms that collaborate with Sanford-Burnham will not face a cultural divide. A blend of academic and industrial scientists at Sanford-Burnham makes it easier to do business with them. About one-fifth of Sanford-Burnham’s drug discovery researchers have backgrounds in the pharmaceutical and biotechnology industry.
“They bring the discipline and competency of industrial settings,†says Dr. Reed, such as being accustomed to working toward milestone-driven timelines on projects. The same timeline-driven management style guides the workflow at the CPCCG to fulfill contracts with the NIH and the NCI.
Another reason to partner with Sanford-Burnham is its strong reputation for scientific publishing, Dr. Reed says. For the past decade, Sanford-Burnham scientists have ranked first worldwide for scientific citations in biology and biochemistry, according to Thomson Reuters Journal Citation Reports. “The work we do is high quality and has a high impact,†Dr. Reed adds. In addition, Sanford-Burnham ranks second in the number of U.S. patents received for the amount of grant dollars awarded.
Collaborators can work with Sanford-Burnham researchers in California or Florida. The East and West Coast laboratories operate as a fully integrated, single organization, and researchers conduct daily teleconferences. Sanford-Burnham is exploring opportunities to build on this infrastructure to expand to other sites such as Asia in the future.
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AFraxis CEO Outlines Biotech’s Success With Ultra-Lean Pre-Clinical R&D in Russia
Last Updated on Wednesday, 12 May 2010 02:49 Written by Editor Wednesday, 12 May 2010 02:49
AFraxis, a mostly stealthy San Diego biotech, is getting ready to come out with a big announcement in the next week or so, but CEO Jay Lichter previewed some key parts of the story yesterday during a presentation before the San Diego Venture Group. He says the biotech has completed pre-clinical testing of a promising compound for treating a form of autism related to Fragile X syndrome.
Lichter, who does double duty as a managing partner of San Diego-based Avalon Ventures, founded aFraxis in 2007—shortly after researchers identified a possible drug target for Fragile X, a family of related mental disorders caused by a defect (or multiple defects) in a single gene on the X chromosome.
Of course, finding a compound that fits a single molecular target (the way a key fits into a lock) is no simple matter. The process can require screening millions of compounds, and then researchers must determine if candidate compounds are reasonably safe for initial use in humans and show the relevant pharmacological activity that justifies commercial development.
“The goal is to make a single exploratory compound and test it in a mouse, and we’ve done that,†Lichter says. The aFraxis CEO didn’t provide a lot of new details about the science. The target, which was identified at MIT in Nobel laureate Susumu Tonegawa’s laboratory, is PAK, a specific group of enzymes that catalyze neural reactions. Lichter says the same mechanism appears to be in play with schizophrenia. As Denise reported earlier this month, Fragile X Syndrome, which is the most common known cause of autism, is believed to be caused by defects in the gene that produces this group of enzymes.
Lichter’s presentation was instead focused mostly on the ultra-lean company-building approach aFraxis has taken to get this far. After three years, he says the biotech has only a handful of employees, and Avalon has invested a total of roughly $6 million to basically get to a stage where the company could submitt an application to begin clinical trials. “We started from scratch from a paper in PNAS (Proceedings of the National Academy of Sciences,†Lichter says.
The pre-clinical research was done in record time—and at a savings of roughly $4 million—by joining forces with Torrey Pines Investment, Lichter says. Torrey Pines Investment, a San Diego life sciences investment firm, happens to own a full-service contract research organization near Moscow. AFraxis plans to begin tests in Russia in 2011 to evaluate the drug’s safety in humans, Lichter says. If all goes as planned, he says tests in Fragile X patients in Moscow will follow.
Nicolay Savchuk, a Russian-born mathematician and director of Torrey Pines Investment who also participated in the presentation, says his firm uses its ties with the Moscow-based Chemical Diversity Research Institute to focus “on the gap where [potential drug] compounds are and where they need to be.†Savchuk says his firm likes to invest in potential drug candidate “assets†and use its R&D capabilities to produce “data packages†that provide the validation necessary to eventually turn its assets into drugs.
Savchuk says the deal with Avalon and aFraxis was “unusual and out-of-the-box thinking†made possible because “Jay was very seductive†and offered Torrey Pines an opportunity to make a direct investment in aFraxis. In exchange for an equity stake in the San Diego biotech, Savchuk says his firm guaranteed to cover the costs of the pre-clinical research and development that was done by the Russian CRO.
“I would not say it’s a one-size-fits-all model,†Savchuk says. “But it is a way to do more.â€
Lichter added that he personally reviewed the capabilities of the Russian CRO, and was deeply impressed by the institute’s “top-notch’ capabilities in medicinal chemistry, biology, and related fields of drug research and development. He says he also was assured by the fact that Savchuk lives and works “just down the street.†Lichter says the Russian CRO’s cost was competitive with Asian firms, but that Savchuk’s personal involvement was a crucial factor—and a principal reason why Lichter could not envision doing the same work with an unfamiliar CRO in India or China.
“There’s something to be said about good neighbors,†Savchuk agreed. “We saw these target-to-clinic capabilities [that we have] as a convenient way to de-risk [biotech] investments. It made sense to us and our partners to streamline costs as much as possible.â€
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« Community Group Loses City Funding More Restaurants on Noe Valley’s 24th Street? » UCSF Lab Uses Brains & Street Smarts to Fight Deadly Parasite
Last Updated on Wednesday, 12 May 2010 02:46 Written by Editor Wednesday, 12 May 2010 02:46
A few years ago a chemist made an offer under the table to Jim McKerrow, a professor at UC San Francisco’s Mission Bay campus. McKerrow accepted and drove down to South San Francisco, backed his car up to a loading dock, filled the trunk, and drove away.
“Suddenly I think, oh wow. What if I get stopped by the highway patrol and they open the trunk and there’s all these vials with white powder,†he said, recalling the incident recently. “Now officer, these are protease inhibitors,†he joked.
Back in the mid-1990s, McKerrow adopted another protease inhibitor, K777, in a similarly altruistic maneuver with Jim Palmer, a chemist then working at the now defunct Khepri Pharmaceuticals.
Today, that compound has become a promising candidate in the fight against an infectious parasite that has been found in the Bay Area blood supply and affects millions of victims in Latin America. The culprit—Trypanosoma cruzi (trip-PAN-o-soma CREW-see) —causes the potentially-fatal Chagas disease.
If K777 is successful, which won’t be known until it goes through lengthy clinical trials, it will be the first drug out of UCSF developed independently from industry. In this case, that research was conducted by McKerrow’s lab and its collaborators at the Sandler Center for Basic Research into Parasitic Diseases, a consortium devoted to drug development for neglected diseases.
The latter are infections that are endemic but primarily affect poor people. With Chagas, it’s 8 to 12 million of them, nearly all having lived in rural Latin America at some point in their lives.
An obsolete Brazilian 10,000 cruzado note reflects the importance of the disease in that country, where it was first discovered.
“Instead of on American money – e pluribus unum – here is the life cycle of the parasite sucking blood from someone’s skin,†McKerrow said, pulling a bill out of his desk drawer and pointing to money, which shows a drawing of a benchuca and the skin of its victim, complete with bite mark and parasite-rich feces.
Spread By A Bloodsucking Vector
The T. cruzi parasite – a single-celled eukaryote – is spread by a bloodsucking subfamily of assassin bug called a benchuca, or kissing bug. It bites near a sleeping victim’s eye or mouth, hence its name.
Every time a benchuca has a blood meal, it also defecates. T. cruzi moves from bug to human host when the victim inadvertently scratches the its poop into the bite wound or a mucus membrane.
The Centers for Disease Control and Prevention believe that almost all infections happen outside of the United States, but the parasite, and the insect that spreads it, live in the Southwest and some parts of California. It can also infect animals.
If untreated, 20 to 30 percent of its victims will develop significant, sometimes fatal heart disease, according to the CDC.
No Financial Incentives to Study Chagas
Because the poor are most affected, Chagas isn’t an interesting investment for pharmaceutical development, but it remains important to researchers and countries like Brazil, Argentina, and Bolivia, which have pockets of very high incidence. It’s that importance that leads some to make calls to fellow chemists like McKerrow.
Labs have no financial incentive to look into alternatives to the available treatment for the parasite — nasty drug regimens developed around WWII that have serious side effects including vomiting, psychiatric effects, and nerve damage. But still, scientists remain interested and aware that the latter might be improved on.
So when lawyers for the closing South San Francisco life sciences company told their scientists to destroy the compounds they had been working on to avoid any legal problems, the chemist thought it worth the risk to call McKerrow.
Some of these otherwise doomed compounds, he or she suspected, might be useful to the Sandler Center in fighting parasitic diseases like Chagas and malaria. McKerrow declined to name the chemist.
“It would be a terrible shame to waste stuff in which millions of dollars had been poured into,†Jim Palmer said generally about drugs developed in industry that might get thrown away.
Years earlier, Palmer made a batch of K777 for McKerrow in his free time, hoping the compound would have potential to help treat parasitic infections.
Palmer now works in Australia and said that everything he did with McKerrow was above board, though there are indications that some higher ups in his company at the time – long since dissolved – were uninformed about the relationship initially. “I don’t know anything about that – I don’t remember,†Palmer said.
Palmer was happy about the compound´s progress. He said he named after he saw the very first Boeing 777 airplane waiting to enter service at Dulles International Airport. “It’s like my child,†he said.
K777 was one of about 20 compounds – initially investigated for applications like cancer and arthritis – that were handed over to McKerrow to match against a chemical produced by the Chagas disease parasite.
McKerrow said that the compound has since been legally secured, safe from anyone being able to take out a patent and charge huge sums for it if it.
Though getting drug company throwaways helps, having promising compounds is merely one of many steps in a long and expensive drug development process.
Sandler Center researcher at a chemical hood.
Researchers screened thousands of compounds along the way. Tests for the disease had to be created, as did an animal model, which were designed through the devoted efforts of scientist couple Patricia Doyle-Engle and Juan Engle, according to McKerrow.
The Sandler Center targeted Chagas in particular because Latin American countries have basic infrastructure, like clinics, to distribute medicines once they are developed.
McKerrow said there won’t be a vaccine, since vaccines function to boost immune function, and in later stages of the disease, the host’s own immune response to T. cruzi helps damage heart tissue. Furthermore, there are wild animals like armadillos that are reservoirs for the disease. It’s impossible to eradicate.
Instead, researchers at the Sandler Center are looking at possible drug treatment – protease inhibitors – that stop the action of a chemical the parasite requires throughout its life cycle.
So far, K777 has been shown to be effective in animal tests. The next step is a clinical trial in humans. McKerrow said that the next hurdle is raising roughly $350,000 to pay for manufacturing the drug for such a study according to FDA standards.
Parasites in the Blood Supply
Meanwhile, on the local level, other researchers are tracking Chagas through blood donations.
Studies conducted by San Francisco-based Blood Systems Research Institute found that one out of every 16,000 donors in the San Francisco area tested positive for the parasite. That’s about double the overall U.S. rate.
The CDC estimates roughly 300,000 immigrants have the parasite in the United States.
“Nobody is legally required to screen for T. cruzi in the U.S.,†said Brian Custer, an associate investigator at the institute. He estimated 75 to 80 percent of blood banks nationwide are screening for it, and probably all California blood banks screen for it.
He said he didn’t know anybody that was doing really good outreach, adding that the institute tried to form outreach partnerships with local organizations and clinics, but it was “very, very unsuccessful.â€
The American Red Cross and the institute are the largest blood research entities in the country and the only blood banks studying the infection. Custer said the Blood Systems Research Institute is in an ongoing study of the parasite in Brazil, because little data exists on how Chagas disease progresses after initial infection.
“We really don’t know how it’s contributing to the overall burden of heart disease in the United States,†Custer said.
Rare cases of transmission have occurred in this country. However, infection is closely associated with substandard housing – the benchuca likes crevices that exist in thatched housing – and the vast majority of infections are linked to time spent in certain rural areas of Latin America.
Areas of Argentina have some of the highest prevalence of infection, yet “the likelihood of someone in Buenos Aires having T. cruzi is about the same as someone in San Francisco having the infection,†Custer cautioned.
It’s a disease, like many, with a long tail and may have felled one of the most famous scientists of all.
Charles Darwin wrote about being bitten by a benchuca and suffered from a mysterious illness his whole life. He died from heart failure, and some believe he may have had Chagas.
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Evotec Extends and Broadens Research Agreement with Cubist Pharmaceuticals
Last Updated on Wednesday, 12 May 2010 02:37 Written by Editor Wednesday, 12 May 2010 02:37
Evotec AG / Evotec Extends and Broadens Research Agreement with Cubist Pharmaceuticals processed and transmitted by Hugin AS. The issuer is solely responsible for the content of this announcement.
- Collaboration expanded to include integrated fragment-based drug discovery activities on additional antibacterial targets – Hamburg, Germany – 25 February 2010: Evotec AG (Frankfurt Stock Exchange: EVT, TecDAX) today announced that it has extended its research agreement with Cubist Pharmaceuticals, Inc. (NASDAQ: CBST) to the end of 2010. Under the contract extension, Evotec will provide additional fragment-based drug discovery expertise using its proprietary platform, EVOlution(TM), which includes fragment screening, structural biology and protein crystallography, to discover and profile novel compounds against additional antibacterial targets selected by Cubist.
Evotec and Cubist have collaborated since July 2009, successfully progressing drug discovery programmes. Over the course of 2010, Evotec will continue and expand its support of Cubist’s discovery activities. A key benefit of Evotec’s fragment-based drug discovery platform is its versatility, combining biochemical and biophysical techniques including nuclear magnetic resonance (NMR), surface plasmon resonance (SPR) and x-ray crystallography, thus allowing the design of target-specific strategies.
Dr Mark Ashton, Executive Vice President, Business Development of Evotec commented: “This is further validation of our expertise and capabilities in fragment-based drug discovery. We enjoy the close and productive relationship we have with Cubist’s scientists and look forward to carry on adding significant value to their portfolio of antibacterial programmes.” No financial details are disclosed.
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About EVOlutionTM EVOlutionTM is Evotec’s fragment-based drug discovery platform which combines biochemical and biophysical techniques including nuclear magnetic resonance (NMR), surface plasmon resonance (SPR) and x-ray crystallography for the screening of low molecular weight compounds and fragments. By the combination of the orthogonal screening technologies, Evotec’s fragment screening platform is capable of screening a more diverse set of biological targets than other fragment screening approaches, as well as being able to screen the fragments in a high-throughput mode. The benefit of this is the ability to identify active fragments for numerous classes of biological targets in a short space of time.
For further information, please see: www.evotec.com/fragment-based drug discovery
About Fragment-based Drug Discovery Fragment-based drug discovery (FBDD) is a new paradigm in drug discovery that utilises very small molecules – fragments of more complex molecules – to generate efficient starting points for drug discovery. This approach thus provides the opportunity to effectively manage the molecular weight and overall complexity of drug candidates, a recognised success factor in drug development.
Contact Evotec AG: Dr Werner Lanthaler, Chief Executive Officer, Phone: +49.(0)40.56081-242, werner.lanthaler@evotec.com
and internationally.
The list of risks above is not exhaustive. Our most recent Annual Report on Form 20-F, filed with the Securities and Exchange Commission, and other documents filed with, or furnished to the Securities and Exchange Commission, contain additional factors that could impact our businesses and financial performance.
We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any such statements to reflect any change in our expectations or any change in events, conditions or circumstances on which any such statement is based.
source: tmcnet.com evotec.com
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Pharmatek Laboratories Receives DEA Registration for Handling Controlled Substances
Last Updated on Wednesday, 12 May 2010 02:35 Written by Editor Wednesday, 12 May 2010 02:35
Pharmatek Expands its Capabilities in Providing Comprehensive Drug Development and Manufacturing Services
SAN DIEGO, Feb. 17 /PRNewswire/ — Pharmatek Laboratories, Inc., a premier contract development and manufacturing organization supporting the pharmaceutical industry, announced that it has successfully met Drug Enforcement Agency (DEA) requirements to be registered for the development and manufacture of Schedule IV and V controlled substances.”Based on the needs of our clients, Pharmatek has put significant systems in place for the handling, inventory, development and manufacture of controlled substances,” said Kevin Rosenthal, Director of Manufacturing.  “Being registered by the DEA validates our facility design, security systems, and procedures for manufacturing, handling, storage and disposal meet the stringent requirements of the DEA.”
Controlled substances are designated as Schedule I-V according to their medical use, potential for abuse and safety or dependence liability. In order to research, manufacture or distribute a controlled substance, a person or entity must be audited and registered by the DEA.
“Our goal is to continue to strive to meet the needs of our existing and prospective clients by adding to our capabilities in pharmaceutical chemistry development and manufacturing,” said Timothy Scott, President at Pharmatek. “As a client-centric organization, our success is predicated on our ability to serve our clients. We are happy to bring this additional capability to Pharmatek in order to serve that purpose.”
About Pharmatek Laboratories, Inc.
Pharmatek Laboratories Inc. is a premier pharmaceutical chemistry development company providing full-service pharmaceutical chemistry product development for the pharmaceutical industry. Pharmatek focuses on bringing client compounds from discovery to the clinic with services that include compound selection, analytical development, preformulation testing, formulation development, GMP manufacturing, stability storage and testing, and cytotoxic and high-potency development.
Statements contained in this media release which are not historical facts may constitute forward-looking statements. All forward-looking statements are subject to risks and uncertainties which could cause actual results to differ from those projected including sales forecasts and strategic expansion. The trademarks Pharmatek, Pharmatek Laboratories, Inc., Hot Rod Chemistry, Pharmatek Formulation Screening, Pharmatek University and PTEK U are all property of Pharmatek Laboratories, Inc. Additional information about Pharmatek Laboratories may be obtained at the Web site http://www.pharmatek.com or by calling 858-805-6383.
source: fiercebiotech.com
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Pyrazole compound BPR1P0034 with potent and selective anti-influenza virus activity
Last Updated on Wednesday, 12 May 2010 02:34 Written by Editor Wednesday, 12 May 2010 02:34
Influenza viruses are a major cause of morbidity and mortality around the world. More recently, a swine-origin influenza A (H1N1) virus that is spreading via human-to-human transmission has become a serious public concern.
Although vaccination is the primary strategy for preventing infections, influenza antiviral drugs play an important role in a comprehensive approach to controlling illness and transmission. In addition, a search for influenza-inhibiting drugs is particularly important in the face of high rate of emergence of influenza strains resistant to several existing influenza antivirals.
Methods: We searched for novel anti-influenza inhibitors using a cell-based neutralization (inhibition of virus-induced cytopathic effect) assay.
After screening 20,800 randomly selected compounds from a library from ChemDiv, Inc ., we found that BPR1P0034 has sub-micromolar antiviral activity. The compound was resynthesized in five steps by conventional chemical techniques.
Lead optimization and a structure-activity analysis were used to improve potency. Time-of-addition assay was performed to target an event in the virus life cycle.
Results: The 50% effective inhibitory concentration (IC50) of BPR1P0034 was 0.42 +/- 0.11 uM, when measured with a plaque reduction assay.
Viral protein and RNA synthesis of A/WSN/33 (H1N1) was inhibited by BPR1P0034 and the virus-induced cytopathic effects were thus significantly reduced. BPR1P0034 exhibited broad inhibition spectrum for influenza viruses but showed no antiviral effect for enteroviruses and echovirus 9.
In a time-of-addition assay, in which the compound was added at different stages along the viral replication cycle (such as at adsorption or after adsorption), its antiviral activity was more efficient in cells treated with the test compound between 0 and 2 h, right after viral infection, implying that an early step of viral replication might be the target of the compound. These results suggest that BPR1P0034 targets the virus during viral uncoating or viral RNA importation into the nucleus.
Conclusions: To the best of our knowledge, BPR1P0034 is the first pyrazole-based anti-influenza compound ever identified and characterized from high throughput screening to show potent (sub-uM) antiviral activity.
We conclude that BPR1P0034 has potential antiviral activity, which offers an opportunity for the development of a new anti-influenza virus agent.
Author: Shin-Ru ShihTzu-Yun ChuGadarla Randheer ReddySung-Nain TsengHsiun-Ling ChenWen-Fang TangMing-sian WuJiann-Yih YehYu-Sheng ChaoJohn HsuHsing-Pang HsiehJim-Tong Horng
Credits/Source: Journal of Biomedical Science 2010, 17:13
source: 7thspace.com
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Genentech and UCSF’s Small Molecule Discovery Center Ink Deal Targeting Neurodegenerative Diseases
Last Updated on Wednesday, 12 May 2010 02:26 Written by Editor Wednesday, 12 May 2010 02:26
The University of California, San Francisco and Genentech are partnering to discover and develop drug candidates for neurodegenerative diseases. The company will support the work of several researchers at the UCSF Small Molecule Discovery Center (SMDC) to progress prior SMDC research and Genentech discoveries.
In addition to receiving financial support for its research function, UCSF has the potential for further funding in excess of $13 million if certain development and commercial milestones are met. UCSF will also earn royalties on sales of any resulting products.
This is the first major collaboration that the SMDC has formed with an industry partner, according to Jim Wells, Ph.D., who founded the center in 2005 and serves as its director. Dr. Wells and the center’s associate directors Adam Renslo, Ph.D., and Michelle Arkin, Ph.D., will lead the project.
“What is transformative about this agreement from the university’s perspective is that it is a true collaboration between UCSF and Genentech scientists with the intent to generate drug candidates,†Dr. Wells comments. “This is different from a standard out-license or simple research collaboration.
“Finding targeted compounds is a major obstacle in the drug discovery process in part because most academic researchers don’t have access to this type of facility,†Dr. Wells adds. “This collaboration shows how a center like the SMDC can help support the path from new biology into therapeutic products to help improve patients’ lives.â€
The center is based on high-throughput screening, medicinal chemistry, and fragment-based screening, including a novel approach called tethering, which Dr. Wells pioneered in his previous role as founder, president, and CSO at Sunesis Pharmaceuticals. SMDC offers all UC biomedical researchers access to high-throughput screening and follow-up medicinal chemistry technologies. The center performs biochemical and cell-based assays using liquid-handling robots and a screening library of more than 180,000 compounds. Over the past four years, the center has grown to 18 biologists and chemists, many reportedly with pharmaceutical experience.
SMDC’s arrangement with Genentech builds on the existing master agreement between the company and UCSF, which allows the two to collaborate in a streamlined manner. “To date we have entered into more than 15 research collaborations with UCSF across several therapeutic areas,†comments Marc Tessier-Lavigne, Ph.D., evp, research and CSO of Genentech.
source: genengnews.com
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Study looks at shifting energy metabolism
Last Updated on Wednesday, 12 May 2010 02:25 Written by Editor Wednesday, 12 May 2010 02:25
U.S. scientists say they are using a novel screening technique to identify new effects of drugs in shifting cellular energy metabolism.Researchers at Massachusetts General Hospital, which led the study, said drugs that target the way cells convert nutrients into energy could offer new approaches to treating a range of conditions, including heart attack and stroke.
The team said it identified several FDA-approved agents, including an over-the-counter anti-nausea drug, that can shift cellular energy metabolism processes in animals.
“Shifts in cells’ energy production pathways take place naturally during development and in response to demanding activities — like sprinting versus long-distance running,” said Dr. Vamsi Mootha, the lead investigator. “They are also known to be involved in several disease states. We wanted to identify compounds that can safely induce this shift … and investigate their therapeutic potential in animal models.”
The researchers said their findings, which may lead to new therapeutic strategies to treat several serious health problems, appear in the early online edition of the journal Nature Biotechnology.
source: upi.com
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Nausea drug may treat heart disease
Last Updated on Wednesday, 12 May 2010 01:53 Written by Editor Wednesday, 12 May 2010 01:53
American scientists have identified new effects of drugs approved by Food and Drug Administration (FDA), which can help shift cellular energy metabolism and may even come useful in the treatment of cardiovascular disease.
The findings of the study team, led by Massachusetts General Hospital (MGH) researchers, have appeared in Nature Biotechnology . One of the key findings of the study was meclisine, a well-known nausea drug, may help treat heart disease and stroke. Initial studies in animals using meclisine, a drug commonly used to treat nausea and vertigo, have given favourable results in treating cardiovascular diseases and stroke. Vamsi Mootha of the MGH Center for Human Genetic Research, who led the study, said, ‘Shifts in cells’ energy production pathways take place naturally during development and in response to demanding activities – like sprinting versus long-distance running. They are also known to be involved in several disease states.
“We wanted to identify compounds that can safely induce this shift – those that have previously been discovered are too toxic – and investigate their therapeutic potential in animal models.” Usually cells convert nutrients into energy by relying on two cellular processes. One involves the uptake of sugars that are broken down in the cytoplasm into a molecule called lactate by a process called glycolysis, which quickly yields a small amount of ATP, the enzyme that provides cellular energy. Alternatively, sugars and proteins can be processed in cellular structures called mitochondria to release greater amounts of ATP through a more efficient process called cellular respiration.
In cancer cells and other rapidly proliferating cells, energy is produced predominantly by glycolysis, suggesting that a shift away from that mechanism might suppress tumour growth. Previous animal studies suggested that a reduction in mitochondrial respiration could mimic a process called ischemic preconditioning, in which brief episodes of ischemia – a reduction in blood flow – actually protect tissue against being damaged if its blood supply is later cut off completely.
To look for compounds that shift cells from respiration to glycolysis, Mootha’s team devised a unique screening strategy. The scientists cultured skin cells in two different nutrient environments – glucose, which provides energy through both glycolysis and respiration, or galactose, which forces cells to rely on mitochondrial respiration alone. A drug that redirects energy metabolism from respiration to glycolysis would stop growth in the galactose- cultured cells while having little effect on cells grown in glucose. Their initial screen of almost 3,700 compounds, including nearly half of all FDA-approved drugs, found several drugs known to inhibit cellular respiration on one end of the scale and several anti-cancer drugs that halt the growth of rapidly proliferating cells at the other, which verified the approach.
Because most agents known to mimic ischemic preconditioning in animal models are too toxic to use in human patients, the researchers were quite eager to find drugs that cause subtle metabolic shifts. The screen identified eight approved drugs that produced a less pronounced but still significant shift away from cellular respiration. One of those agents was meclisine.
To study meclisine’s potential to prevent tissue damage in heart attack or stroke, Mootha’s team joined hands with University of Rochester researchers who had developed rat models of heart attack damage and an MGH Pathology group with a mouse model of stroke damage. Blinded experiments using both animal models showed that pretreatment with meclisine dramatically reduced ischemic damage to cardiac cells in the heart attack model and to brain cells in the stroke model. They also discovered that meclisine’s ischemia protective effects do not appear to involve its known mechanisms.
While the study results suggest that treatment with drugs like meclisine may someday be useful for reducing the damage associated with heart attack or stroke, Mootha believes much additional study is needed. He said, “Before we can think about human studies, we need to do rigorous animal testing to determine optimal, safe dosing regimens and learn more about how this drug works.”
source: indiatimes.com
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Home » content Shifting cellular energy metabolism may help treat cardiovascular disease
Last Updated on Wednesday, 12 May 2010 01:49 Written by Editor Wednesday, 12 May 2010 01:49
Drugs that target the way cells convert nutrients into energy could offer new approaches to treating a range of conditions including heart attack and stroke. Using a new way to screen for potential drugs, a team led by Massachusetts General Hospital (MGH) researchers has identified several FDA-approved agents, including an over-the-counter anti-nausea drug, that can shift cellular energy metabolism processes in animals. Their findings, being published online in Nature Biotechnology, may open the door to new therapeutic strategies for several serious health problems.
“Shifts in cells’ energy production pathways take place naturally during development and in response to demanding activities — like sprinting versus long-distance running. They are also known to be involved in several disease states,” explains Vamsi Mootha, MD, of the MGH Center for Human Genetic Research, who led the study. “We wanted to identify compounds that can safely induce this shift — those that have previously been discovered are too toxic — and investigate their therapeutic potential in animal models.”
Normally cells convert nutrients into energy by relying on two cellular processes. One involves the uptake of sugars that are broken down in the cytoplasm into a molecule called lactate via a process called glycolysis, which quickly yields a small amount of ATP, the enzyme that provides cellular energy. Alternatively, sugars and proteins can be processed in cellular structures called mitochondria to release greater amounts of ATP through a more efficient process called cellular respiration.
In cancer cells and other rapidly proliferating cells, energy is produced predominantly by glycolysis, suggesting that a shift away from that mechanism might suppress tumor growth. Previous animal studies suggested that a reduction in mitochondrial respiration could mimic a process called ischemic preconditioning, in which brief episodes of ischemia ? a reduction in blood flow ? actually protect tissue against being damaged if its blood supply is later cut off completely.
To search for compounds that shift cells from respiration to glycolysis, Mootha’s team devised a novel screening strategy. They cultured skin cells in two different nutrient environments ? glucose, which provides energy through both glycolysis and respiration, or galactose, which forces cells to rely on mitochondrial respiration alone. A drug that redirects energy metabolism from respiration to glycolysis would stop growth in the galactose-cultured cells while having little effect on cells grown in glucose. Their initial screen of almost 3,700 compounds, including nearly half of all FDA-approved drugs, identified several drugs known to inhibit cellular respiration on one end of the scale and several anti-cancer drugs that halt the growth of rapidly proliferating cells at the other, which verified the approach.
Because most agents known to mimic ischemic preconditioning in animal models are too toxic to use in human patients, the researchers were most interested in finding drugs that cause subtle metabolic shifts. The screen identified eight approved drugs that produced a less pronounced but still significant shift away from cellular respiration. One of those agents was meclizine, an over-the-counter drug used to treat nausea and vertigo ? suggesting that it passes the blood-brain barrier ? with few negative side effects.
To investigate meclizine’s potential to prevent tissue damage in heart attack or stroke, Mootha’s team collaborated with University of Rochester researchers who had developed rat models of heart attack damage and an MGH Pathology group with a mouse model of stroke damage. Blinded experiments using both animal models showed that pretreatment with meclizine dramatically reduced ischemic damage to cardiac cells in the heart attack model and to brain cells in the stroke model. They also found that meclizine’s ischemia protective effects do not appear to involve its known mechanisms.
While the study results suggest that treatment with drugs like meclizine may someday be useful for reducing the damage associated with heart attack or stroke, Mootha stresses that much additional study is needed. “Before we can think about human studies, we need to do rigorous animal testing to determine optimal, safe dosing regimens and learn more about how this drug works,” he says. He also notes that the drug-screening strategy developed by his team could help to identify previously unsuspected beneficial or detrimental effects of other approved drugs.
Mootha is an associate professor of Systems Biology at Harvard Medical School and an associate member of the Broad Institute of MIT and Harvard. Co-lead authors of the Nature Biotechnology article are Vishal Gohil, PhD, and Sunil Sheth, MD, MGH Center for Human Genetic Research (CHGR). Additional co-authors are Roland Nilsson, PhD, Fabiana Perocchi, PhD and William Chen, MGH-CHGR; Jeong Hyun Lee, PhD, and Cenk Ayata, MD, MGH Pathology; Andrew Wojtovich and Paul Brookes, PhD, University of Rochester Medical Center; and Clary Clish, PhD, Broad Institute. The study was supported by grants from the American Diabetes Association and the Smith Family Foundation.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $600 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.
source: scienceblog.com
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