Bio Screening Industry News

From Focused Compound Libraries to optimised Hit-to-Lead - that’s the motto of IQPC’s 4th international conference on “Compound Libraries” (formerly “Focused Compound Libraries”). Nowadays the pharmaceutical industry is under enormous pressure, and the key for the industry to survive is faster and more efficient drug discovery. To improve their lead generation process and library, pharmaceutical companies need to choose the correct library design from the very beginning. Also, they need to integrate new compounds and collections into their library design to guarantee its continuous improvement. However, urgent questions still remain: How can you find the ideal library size to assure diversity while keeping focused? Can fragment based screening speed up the discovery process? How can you guarantee the best screening outcome analysis to ensure lead optimization?

After concentrating on focused compound libraries in the past years, this year presentations will cover the design and enhancement of different kinds of libraries as well as the possibilities of hit-to-lead optimization.

Maximize your knowledge of the latest advances in intelligent library design:

• Explore how to efficiently integrate new compounds and collections to improve the lead generation process
• Learn how to build up an effective collection of compounds in your company to guarantee physical quality and quantity of the compounds
• Hear about enhanced screening methods such as fragment-based screening to reduce complexity in the screens
• Successfully enlarge your compound collection by utilising novel structures and multi-component reactions in library design
• Enhance your Hit-to-Lead ratio through advances in library design, screening methods and structure based drug discovery approaches

Experts from international companies such as Pfizer, AstraZeneca, Merck, Grünenthal, Sanofi-Aventis and many more will report about first-hand experiences and best practices.

Full speaker line-up:

• Sanofi-Aventis Gruppe, Germany
• AstraZeneca Ltd., UK
• Merck Serono, Germany
• Basilea Pharmaceutica International AG, Switzerland
• Organon Laboratories Ltd., UK
• GenKyotex S.A., Switzerland
• Carlsberg Laboratory, Denmark
• Chemical Genomics Centre of the Max-Planck-Society, Germany
• AstraZeneca, R&D Mölndal, Sweden
• AnalytiCon Discovery GmbH, Germany
• Asinex Ltd., Russia
• TU Vienna, Austria
• BioFocus DPI Limited, UK
• Solvay Pharmaceuticals BV, Netherlands
• Grünenthal GmbH, Germany
• Novartis, Switzerland
• Bayer CropScience AG, Germany
• Pfizer Ltd., UK

http://www.iqpc.com/ShowEvent.aspx?id=113724

By extracting information from a freely-available chemical database, Italian forensic scientists have come up with a simple but highly effective method for identifying unknown toxicological compounds in biological samples.

A central component of forensic analysis and drug testing, toxicological analyses of biological samples have traditionally been conducted using gas chromatography/mass spectrometry (GC/MS), with compounds identified by comparing the resultant mass spectra with reference mass spectra in spectral databases.

Although effective at identifying toxicological compounds, this approach has certain limitations, such as the fact that GC/MS is not very good at detecting polar and non-volatile compounds. Liquid chromatography (LC) coupled with MS offers a more flexible alternative, able to identify both polar and non-volatile compounds. However, it suffers from an inability to produce as detailed mass spectra as GC/MS, which has prevented the construction of large spectral databases for LC/MS. According to Aldo Polettini of the University of Verona, LC/MS databases generally contain spectra for only around 1200 compounds, compared to spectra for tens of thousands of compounds in GC/MS databases.

In recent years, however, a type of MS known as time-of-flight (TOF) has opened up another way of identifying toxicological compounds with LC/MS. TOF-MS measures the masses of charged molecules based on the time they take to travel along a chamber to a detector under the influence of an electric field, with smaller molecules travelling faster than larger molecules. This allows it to make measurements of molecular mass that are so accurate that they can be used to determine a compound’s chemical formula, and thereby also its identity.

The problem is that there aren’t any major databases containing information on molecular mass and chemical formulae specifically for toxicological compounds, so Polettini decided to create one. The easiest way to do this is to extract data for toxicological compounds from an existing chemical database and Polettini chose to do this with the US National Institutes of Health’s PubChem Compound. This is freely-available on the internet and comprises around 10 million entries, each of which contains information on a compound’s molecular mass and chemical formula.

Together with colleagues, Polettini created a subset of these entries by extracting all the compounds that could be classified as toxicological and then screening them based on their molecular mass and whether they contain elements such as hydrogen, nitrogen or fluorine. This resulted in a subset database containing entries for 50,500 toxicological compounds, including many drug molecules, both pharmaceutical and recreational, pesticides and poisons, as well as metabolites.

‘It contains a large number of metabolites,’ explains Polettini, ‘including glucuronides, which are very important in general unknown screening, especially when metabolite-rich biological matrices are used (e.g. urine).’

Once the database was up and running, all Polettini and his team needed to do to determine the chemical formula of an unknown toxicological compound was to match the molecular mass revealed by TOF-MS with the matching mass in their database. Testing this approach on hair, blood and urine samples from subjects that had taken pharmaceutical or recreational drugs, they found that they were able to identify a whole host of relevant toxicological compounds.

Predictably, the only problem they found was that a specific molecular mass can match more than one chemical formula and a specific chemical formula can match more than one toxicological compound. But the correct compound could usually be pinpointed by simply taking other available information into account, such as some of the spectral data produced by TOF-MS.

A molecule’s retention time in LC can also offer a way to chose between competing identities. To this end, Polettini is now attempting to enhance the database by incorporating an algorithm for estimating the retention time for proposed compounds. These estimates can then be compared with the actual retention time of the detected compound to help reveal the correct identity.

CHARLOTTE, N.C., April 8, 2008 (PRIME NEWSWIRE) — Chelsea Therapeutics International, Ltd. (Nasdaq:CHTP) announced that it has acquired full global rights to the I-3D portfolio of orally active, dihydroorotate dehydrogenase (DHODH) inhibiting compounds for the treatment of autoimmune diseases and transplant rejection.

Following a decision to focus its resources on its immunomodulatory compounds, Active Biotech AB has discontinued its participation in the I-3D co-development program and granted Chelsea exclusive global rights to the portfolio in exchange for royalties on future sales. The I-3D portfolio, originally developed by Active Biotech and under joint development by both companies since 2006, consists of an extensive library of therapeutic compounds that have demonstrated, during preclinical testing, potent inhibition of DHODH activity while maintaining PK and safety properties superior to the marketed DHODH inhibitor. Inhibition of DHODH is the rate-limiting step in de novo pyrimidine biosynthesis, which is required for the proliferation of T-cells during clonal expansion. Potential indications for drug candidates in this library include transplant rejection, rheumatoid arthritis, psoriasis and systemic lupus erythematosus (SLE).

“We have greatly enjoyed our collaboration with Active Biotech and respect their decision to focus on their unique quinoline based therapeutic platform,” commented Dr. Simon Pedder, President and CEO of Chelsea. “We continue to believe that the I-3D portfolio of DHODH inhibitors may have value and have identified a cost-effective process for screening molecules in this portfolio which will require only a minimal investment of time and money. The results of this screening will permit us to make more informed decisions regarding our investment in the program for 2009 and beyond.”

About Chelsea Therapeutics

Chelsea Therapeutics is a biopharmaceutical development company that acquires and develops innovative products for the treatment of a variety of human diseases. The Company is currently developing a library of metabolically inert antifolate compounds engineered to have potent anti-inflammatory and anti-tumor activity to treat a range of immunological disorders. Early clinical data suggests that Chelsea’s lead antifolate compound, CH-1504, is a safe and effective treatment alternative to methotrexate for RA and may have further applications for psoriasis, IBD and certain cancers. Chelsea’s antifolate program is complemented by a strategic partnership with Active Biotech AB for the joint development of a portfolio of therapeutics targeting immune-mediated inflammatory disorders and transplantation. In addition to its autoimmune pipeline, Chelsea is developing Droxidopa, an orally active synthetic precursor of norepinephrine, for the treatment of neurogenic orthostatic hypotension. Currently approved and marketed in Japan, Droxidopa has accumulated over 15 years of proven safety and efficacy, historically generating annual revenues of approximately $50 million in Japan.

This press release contains forward-looking statements regarding future events. These statements are just predictions and are subject to risks and uncertainties that could cause the actual events or results to differ materially. These risks and uncertainties include reliance on collaborations and licenses, risks and costs of drug development, regulatory approvals, intellectual property risks, our reliance on our lead drug candidate CH-1504, our history of losses and need to raise more money, competition, market acceptance for our products if any are approved for marketing, reliance on key personnel including specifically Dr. Pedder, management of rapid growth, and the need to acquire or develop additional products.

Federal scientists are collaborating on a new approach to testing the toxicity of chemicals ranging from pesticides to household cleaners. They plan to use new automated high-speed cell tests to get more reliable data faster and more cheaply, and with less reliance on animal testing.

The National Institutes of Health and the U.S. Environmental Protection Agency are partners in the plan. NIH director Elias Zerhouni says scientists will apply technology developed by the two agencies to identify chemicals that might be harmful to humans.

“You could, in a battery of tests, end up with very specific molecular signatures that will be predictive of human toxicology, in ways that you just can’t do in animal testing today,” he said.

Scientists now rely heavily on animal tests to generate chemical toxicity data. That process is expensive, time-consuming and not always the best predictor of effects on humans says Francis Collins, director of the NIH National Human Genome Research Institute.

“There are differences between species. We are not rats and we are not even other primates, and so that [the] desire here is to see if we could do better,” she said. “Ultimately what you are looking for is [whether] this compound does damage to cells.”

The high-speed automated screening looks at the effects of chemical compounds on single human cells rather than on an entire laboratory animal. Researchers expect the new toxicology testing method will expand the number of chemicals tested and reduce the time, money and use of animals. NIH director Elias Zerhouni says it will also generate data more relevant to humans.

“What is being proposed here is to move the 20th century paradigm of testing of one compound at a time in many animals to going to the 21st Century paradigm [that] tests 5,000 to 10,000 compounds against 20,000 conditions in cells that are very specific to human toxicology,” he said.

Since NIH started the National Toxicology Program 30 years ago, it has tested 2,500 chemicals. Using the new automated strategy could get the same job done in a single afternoon.

John Butcher, associate director of the National Toxicology Program, explains that to check the reliability of this approach, scientists will first do a comparative analysis of the 2,500 chemicals previously tested on animals.

“And we can compare the output from these cell-based assays, in terms of whether these chemicals cause cancer, reproductive and developmental effects, neurological effects, immunotoxic effects and various other kinds of toxicity,” he said.

Butcher says the anticipated shift away from animal testing could take many years. Writing in Science Magazine, he says the agencies expect broader participation from public and private partners in the scientific community as the cell-based testing methods are refined and accepted.

A new device invented by researchers at the University of Virginia could save pharmaceutical companies significant time and money in screening potential new drug compounds.

“We want to help the pharmaceutical industry identify effective therapuetic compounds by allowing them to fail early, fail fast, and fail cheap before going to very expensive animal studies,” said Brett Blackman, an assistant professor in biomedical engineering.

Blackman and Brian Wamhoff, assistant professor in the department of medicine (cardiovascular division), have teamed up to create the novel system, HemoShear 2.0, which offers researchers for the first time the ability to observe the behavior patterns of human vascular cells under a variety of blood flow conditions that occur inside the body’s cardiovascular system.

HemoShear 2.0 models the early indicators of atherosclerosis — hardening or narrowing of the arteries — by placing actual human vascular cells (i.e., endothelial and smooth muscle cells) in an environment that mimics an artery with blood flowing through it. Data from the exposure can be measured and recorded.

HemoShear 2.0 can help test the efficacy of therapeutic compounds and aid in early stage toxicity studies. Instead of testing drug compounds on isolated cells, which can produce false negatives, drug companies can use the device to test compounds in a more realistic environment.

“What the pharmaceutical industry lacks is the ability to mimic an organ ex vivo,” Wamhoff said. “We know that as soon as we take an organ and disperse the cells, those cells are no longer like they were in the body. If you apply a novel compound to that cell, the response you get might be real but it’s not meaningful in the context of the disease. When you go to animal studies, that response may not carry over in the blood vessel. It is clear that human-based biomimetic models are needed to fill this gap”

Atherosclerosis is considered the most important underlying cause of heart attack or stroke. The disease tends to occur at locations in the arteries where blood flow is compromised, causing detrimental changes in both the cells lining the interior of blood vessels (endothelial cells) and the cells found in the wall of blood vessels (smooth muscle cells).

Using an MRI, the researchers determined the rhythmic pattern at which blood flows through different arteries in human subjects. “We are then able to simulate the same flow patterns in those areas that are more or less susceptible to atherosclerosis and observe how the cells respond to these flow patterns in HemoShear,” Blackman said.

According to Wamhoff, this kind of modeling offers unique opportunities to observe the cells and their interaction. “Research has been conducted wherein human cells are isolated to observe behavior patterns, but there are no available models that allow one to accurately study the intricate communication between endothelial cells and smooth muscle cells in a setting that mimics actual blood flow in the body.”

This communication is important, the researchers say, because the cells lining the interior of the blood vessels, the endothelial cells, recognize different blood flow patterns imposed upon them and respond by expressing or repressing genes. This, in turn, influences their interactions with the cells found in the walls of blood vessels, the smooth muscle cells — interactions that, the researchers found, may lead to the onset of early-inflammation-associated atherosclerosis in certain arteries.

Using HemoShear 2.0, the researchers have been able to recreate blood flow patterns in bifurcating and bulbous areas like the internal carotid that are more susceptible to the disease (atheroprone areas) and the pipe-like arteries like the common carotid that are less susceptible to the disease (atheroprotective areas).

Using a synthetic elastic layer that is similar to a real blood vessel wall, endothelial cells are plated on the top surface and smooth muscle cells on the bottom surface. Then, the different blood flow patterns modeled from human circulation are applied to the endothelial cells through rotation of a motor-driven cone system. The findings: the blood flow can influence both endothelial and smooth muscle cell behaviors.

When subjected to atheroprotective blood flow patterns, the endothelial cells aligned with the direction of the blood flow, and the smooth muscle cells aligned perpendicularly to the flow as is true in a healthy blood vessel. In stark contrast, the atheroprone type of flow caused the endothelial cells to move away from their parallel structure while smooth muscle cells moved away from their perpendicular structure. This remodeling mimics the early phases of the diseased state of the artery; the blood flow pattern associated with atheroprone areas resulted in inflammation in both cells reminiscent of early hallmarks of atherosclerosis. This was confirmed through evaluating gene and protein expression profiles in both cell types.

“The results of this study validate the use of this novel co-culture system as a relevant biomimetic vascular model for studying early atherosclerotic events,” said Tom Skalak, professor and chair of the U.Va. Department of Biomedical Engineering. “The cells’ responses to these carefully controlled models of blood flow can now be used to develop therapeutic interventions for detection and treatment of vascular diseases — it has the potential to be revolutionary.”

Blackman,Wamhoff, and Dr. Norbert Leitinger (department of pharmacology) have formed a collaborative entity — the Laboratory of Atherogenesis — to begin using the HemoShear system to make these translatable discoveries in atherosclerosis.

A provisional patent has been filed for HemoShear 2.0. The research that HemoShear 2.0 made possible was spearheaded by a biomedical engineering graduate student, Nicole Hastings (’08), and is published in the American Journal of Physiology — Cell Physiology.

Anachem’s unique permanent custom bar coding service utilises vials each with their own individual bar code that guarantee the identity of their contents and position within a stored location

Protect and identify precious samples more effectively within a compound management process using Anachem’s permanent custom bar coding service. Each bar code is made from a ceramic material that is permanently bonded to a glass vial or any glass laboratory product e.g test tubes or bottle in either one dimensional (1D) or two dimensional (2D) forms.

This completely eradicates the need for conventional sticky labels that can come off during storage or use, rendering the valuable contents unidentifiable.

Vials that have a 2D bar code can be read from underneath using a flat-bed scanner while the vial is positioned on an automated system.

For immediate recognition, companies have the option to apply corporate logos or company names to the side of the vials giving a customised, professional appearance.

Anachem’s bar coded vials are compatible with all solvents including DMSO, DCM and methanol, providing an ideal solution for tracing samples in applications including compound management, chemical screening, sample collection for biological fluid testing, compound library manufacture and QC analysis.

The new Anachem CD vials internally dip to a central point, eliminating the waste of precious chemical compounds and offering complete sample recovery.

Conveniently their flat bases allow them to stand upright.

Scientists are hoping to see the dark amongst the light as they scour nature for its next anticancer drug ‘gift’.

A team at the US National Cancer Institute’s Center for Cancer Research (CCR), have developed a way of screening hundreds of thousands of biodiverse samples to find a particular diamond in the rough - a naturally occurring anticancer drug.

The idea isn’t as far-fetched as it might sound, especially when you consider that two widely used anticancer drugs originally came from tree bark and soil bacteria (paclitaxel and rapamycin respectively).

In fact, scientists often turn to natural sources to develop new drugs, and the 220,000 samples collected in the NCI’s Natural Product Repository are derived from marine organisms, microbes, and plant life gathered from locations across the globe.

“The samples in the Repository exist as extracts from specimens that have been collected in the oceans and forests of the world and shipped here - each containing thousands of compounds,” said Dr Barry O’Keefe, an NCI researcher.

“Somewhere among these samples are natural molecules that have been honed by nature that could have great therapeutic value, but finding them amid the clutter of other natural compounds is difficult.”

Their latest natural products screen uses an electrochemiluminescent assay, developed by CCR researcher Dr Allan Weissman, which tags the target proteins and causes them to light up when an electrical current is passed through them. If a molecule inhibits the target, then its activity is blocked and the reaction goes dark.

To verify that the electrochemiluminescent assay worked properly, the Repository team searched for a molecule that inhibits the known ability of MDM2 to signal for the destruction of the tumour suppressor protein p53. In normal cells, MDM2 and p53 exist in a state of benign equilibrium - balanced to assure that cell suicide does not occur.

The researchers screened over 144,000 samples and uncovered almost 2,000 potential hits against MDM2. These were further refined, yielding 372 extracts from which chemists are now isolating active compounds. Among the active compounds recovered, one plant chemical, called sempervirine, was found to induce cell death or apoptosis in cancer cell lines.