Archive for the ‘Discoveries, Innovations and Patents’ Category
Experimental drug shows some benefit for Huntington’s disease
Last Updated on Wednesday, 12 May 2010 01:32 Written by Editor Wednesday, 12 May 2010 01:32
An experimental drug call latrepirdine has produced a small improvement in the mental abilities of some patients with Huntington’s disease, a finding that sets the stage for a larger clinical trial. Although the improvement was modest, the study marks the first time that a drug has been shown to improve brain function in the disorder.
Huntington’s is one of the more common inherited brain disorders. About 25,000 Americans have it and an additional 60,000 carry the defective gene that causes it and will develop the disorder as they age. It strikes between age 30 and 50 and is characterized by jerky, involuntary movements called chorea; loss of control of bodily functions; and dementia, a progressive deterioration of memory and thought processes. The only drug formally approved for treatment of Huntington’s is tetrabenazine, which improves chorea but does nothing for mental faculties.
Latrepirdine was originally developed in Russia nearly three decades ago as a treatment for hay fever, but it is no longer sold anywhere. Russian researchers screening compounds for potential effects on the brain found that it appears to stabilize mitochondria, the power source of brain and other cells. Because of that activity, Medivation Inc. of San Francisco and Pfizer Inc, which purchased the rights to the drug, conducted a Phase 2 clinical trial of the drug in Alzheimer’s patients and found some benefit. A larger Phase 3 trial, required for Food and Drug Administration approval, is now under way and results are expected later this year.
They also began testing it against Huntington’s, which is marked by a deterioration of mitochondria in brain cells. In a Phase 2 trial, Dr. Kurt Kieburtz of the University of Rochester Medical Center and his colleagues studied the drug in 91 Huntington’s patients over a 90-day period. Half received the drug in three daily doses and half received a placebo. The study was primarily a safety trial and the researchers concluded that the drug posed no untoward risks: About 70% of patients receiving the drug reported adverse side effects, but so did 80% of those receiving a placebo.
The drug produced no benefits on motor function, but it did yield an improvement in a mental test called the Mini-Mental State Examination, in which patients answer questions about what year it is and where they are, count backward, and try to recall words they haver recently heard. Patients receiving the drug showed an average improvement of 0.86 point on the 30-point scale, while those on placebo showed an 0.12-point decline. Kieburtz said he was surprised to see the improvement because the exam is a relatively crude test of mental function.
The trial was sponsored by Medivation and Pfizer, which hope to market the drug under the brand name Dimebon. The company now has a larger trial of 350 Huntington’s patients in progress as a final step toward winning FDA approval.
source: latimesblogs.latimes.com
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Eli Lilly and GlaxoSmithKline: A Tale of Two Different Pharmas
Last Updated on Saturday, 24 July 2010 04:09 Written by Editor Wednesday, 12 May 2010 01:10
New models for drug development, especially in big pharma, are being experimented by different companies. Eli Lilly (LLY) and GlaxoSmithKline (GSK) have two different models. These models do not throw out the old ones – but do offer additional routes going forward.
Lilly has a Phenotypic Drug Discover Initiative, (or PD2), launched in 2009. Lilly solicits compounds from other companies so long as they are in certain therapeutic areas (oncology, diabetes, osteoporosis, and Alzheimer’s Disease). Compound structures are sent to Lilly electronically where they are evaluated using modeling and simulation. If the compound passes the screen, the physical compound is sent to Lilly for further testing. If the compound passes the physical test, the fun begins.
All testing by Lilly is free and IP remains with the originating company or institution. What Lilly gets in return is the first right to exclusively negotiate an agreement. If talks break down, the originator keeps all the data generated by Lilly.
Having had some personal experience through my biotechnology company (IMC Biotechnology), I think this is a very interesting approach. We submitted 9 compounds to Lilly and one of them went through the screening process. The software had some minor glitches but the Lilly representatives were very helpful in addressing those glitches.
I think this is a great way for Lilly to expand its repertoire of compounds beyond those invented by its chemists. Certainly one way of going beyond the NIH (not invented here) syndrome.
GSK has come up with an opposite approach where it is offering its library of compounds to researchers in a certain therapeutic area (under-served tropical diseases). For example, it is offering 13,500 compounds that appear to work in malaria. GSK will let other scientists try to develop malaria drugs — free from royalties or other payments to GSK. They were narrowed down from more than 2 million compounds.
More unusual is its open lab project. GSK plans to give up to 60 outside scientists from around the globe access to what it called the “Open Lab,” at an existing company research lab in Spain. Researchers from universities, foundations, etc will be able to use the facilities to try to develop new medicines for diseases plaguing poor countries.
GSK is to start a foundation to fund research and idea sharing, kicking in $8 million initially. It also plans to work with the Emory Institute for Drug Discovery. I have worked a bit with the Emory Institute of Drug Discovery and know they have an excellent drug development team, but have not learnt anything from them about what their exact role in this project is going to be.
While a small fraction of overall R&D efforts, it nevertheless is a significant departure from business as usual. And while GSK does not expect to get royalties, the halo effect, especially with health care reform in the spotlight, cannot be neglected. One could criticize GSK in pointing out that the company does not have much to lose by sharing data in neglected diseases – and that it is not doing so in the more lucrative markets such as oncology. But I doubt that the millions of patients suffering from malaria and TB will support such criticism. New models for drug development, especially in big pharma, are being experimented by different companies. Eli Lilly and GlaxoSmithKline have two different models. These models do not throw out the old ones – but do offer additional routes going forward.
So the two companies have differing strategies that actually could be quite synergistic. Maybe it is time to pay the ultimate compliment and copy each other.
source: seekingalpha.com
Sleep with the Fishes Zebrafish larvae are a surprisingly compatible stand-in for humans as researchers test the next generation of insomnia drugs.
Last Updated on Thursday, 6 May 2010 11:44 Written by Editor Thursday, 6 May 2010 11:44
There’s a new guinea pig in the search for sleep-related drugs: the zebrafish. Researchers at Harvard University have developed a screening tool that tests the effects of thousands of compounds on zebrafish behavior in an effort to discover new pathways that govern sleep. The research, published this week in the journal Science, may result in new drugs to treat insomnia and other sleep-related disorders.
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| Sleepy head: Harvard scientists are using zebrafish as a model to find drug candidates for insomnia and other sleep disorders. Pictured above is the head portion of a zebrafish larva. The zebrafish brain is labeled in green. Credit: Albert Pan and Alexander Schier |
Alexander Schier and his colleagues at Harvard developed an automated system to assess 60,000 distinct sleep-related behaviors in zebrafish, a tropical fish often used in scientific research. After screening 5,600 small molecules on the larvae, the team discovered 463 significant sleep-altering compounds, many of which have been known to have similar effects in humans.
“We didn’t expect as much conservation of the effects of drugs between humans and zebrafish,” says Schier, professor of molecular and cellular biology. “This was a proof of principle that many of the pathways found in humans are conserved in fish.”
Schier says such behavioral similarities may make zebrafish an ideal model for studying how and why humans sleep, mysteries that are largely unsolved. It’s still unclear what molecular mechanisms control sleep and wakefulness. Pinpointing these pathways, and finding drugs to block or promote them, is a major focus for many pharmaceutical companies–sleep drugs generate $7 billion in annual profits in the United States. However, the drug development process is tedious and expensive. Schier believes that testing drug candidates in zebrafish could be a cheap and straightforward alternative to conventional drug screening.
Typically, to test a drug, researchers first study its effects in cultured cells, looking to see if the drug binds successfully to a target receptor or molecule. They then advance the drug to animal experiments, testing behavioral effects in live subjects. But drugs that have certain effects in cultured cells often have unexpected side effects–or no effect–in a live animal.
“The advantage of zebrafish is that you can keep large numbers of animals in a very small space, and raise many, many animals relatively cheaply,” says Schier. Unlike flies and worms, which are often used in the early stages of pharmaceutical research, fish are vertebrates. “Much can be found in zebrafish that is relevant to mammals,” he says.
To screen the drugs, researchers pipetted single zebrafish larvae into a tiny well of a 96-well tray. Each well was injected with a drug, with one drug tested on 10 different larvae. They placed the tray in a recording chamber with infrared and white LED lights and a camera connected to computer software. After lining the tray up with a corresponding grid on the computer screen, researchers programmed the timing of light to simulate day and night. The camera recorded each fish’s activity over two days, and video tracking software plotted out each fish’s movements per second.
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| Z’s for zebrafish: Zebrafish larvae (above) are naturally transparent. Scientists hope to one day study the effects of sleep drugs on the brain and spinal cord, which can be seen in the image above as a long white structure stretching left to right. Credit: Albert Pan and Alexander Schier |
Using clustering algorithms, Schier and his colleagues grouped fish into 60,000 distinct behavioral profiles, depending on various constraints. “When you turn off the light, how often are they active? When they are inactive, how long? That’s what we observe in the fish,” says Schier. “You can measure many different parameters, and that allows you to profile different drugs.”
Anti-inflammatories, such as cytokines, nonsteroidal anti-inflammatory drugs, and cyclosporine, had a surprising effect. Normally, these drugs induce sleep when taken to combat infection such as the flu. However, Schier found that when given to normal, healthy zebrafish, these compounds, or immunomodulators, made fish more active during the day.
“In disease, immunomodulators have been implicated in sleep,” says Schier. “We propose that maybe there’s some baseline function for these immunomodulators during normal sleep and wake cycles.”
Such findings could help researchers identify new molecular players involved in sleep and wakefulness. Irina Zhdanova, associate professor of anatomy and neurobiology at Boston University Medical School, studies the physiological mechanisms of circadian rhythms and sleep in zebrafish. Zhdanova says there are many sleep-related drugs on the market with substantial side effects; these effects might be avoided with better screening tools.
“The huge scope of drugs tested [by Schier's group] shows that zebrafish-based tests can be effectively used to at least prescreen multiple classes of existing drugs and new candidate substances,” says Zhdanova. “[That is] certainly very helpful.”
In the future, Schier says, zebrafish could also be used as a model for testing drugs for human psychiatric diseases like schizophrenia and autism. The idea is to identify genes associated with the human disease, and try to engineer the same genetic defect in zebrafish. Researchers could then look for certain behavioral changes as a result, such as a fish’s sensitivity to touch, or its reaction to visual cues.
“Hopefully there would be a connection between the gene affected, and change in behavior, and one would try to correct the change in behavior by adding particular drugs,” says Schier. “That’s a bit science fiction at the moment, but it is possible.”
source:technologyreview.com
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Hi-tech microscopes make androgen therapy ‘personal’
Last Updated on Thursday, 28 January 2010 06:03 Written by Editor Thursday, 28 January 2010 06:03
HOUSTON — (December 9, 2009) — On rare occasions, an infant is born with outward appearance of a female but the XY chromosomes of a male. If the child has a normal Y chromosome — the chromosome responsible for testicular development — the condition is known as androgen insensitivity syndrome.
Experts estimate such births occur in about one in 20,000 infants. Other children are born with a partial form of the condition that can affect their genitalia and/or fertility, but how many is not known.
The cause is a wide range of androgen receptor (AR) mutations that fail to perceive the presence of the male hormones testosterone and dihydrotestosterone to differing degrees. How to overcome the problem remained a mystery until Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center experts used a high throughput, automated microscopy technique called high content analysis to solve the puzzle. A report of their findings appears in the current issue of PLoS One, an open access journal.
Reverse effect of mutation
They not only identified the functional abnormality of the AR, but also used high content analysis to “personalize” a treatment that reverses the effects of that mutation.
“With this microscopy technique, we have been able to quantify how the receptor moves and functions inside cells taken from children with normal receptors and in those with the mutation,” said Dr. Marco Marcelli, professor of medicine-endocrinology at BCM and a physician at the Michael E. DeBakey Veterans Affairs Medical Center. He and Dr. Michael Mancini, associate professor of molecular and cellular biology at BCM, and director of its Integrated Microscopy Core, are senior authors of the report.
Androgen insensitivity syndrome
They used banked cells taken from patients – both those with the mutation and those without – to study the action of the receptor in cell cultures grown in the laboratory. Dr. Michael J. McPhaul, a collaborator on the study and a professor of internal medicine—endocrinology at The University of Texas Southwestern School of Medicine Dallas, provided the samples from patients with androgen insensitivity syndrome.
“We did this on a cell-by-cell basis, using high content analysis,” said Mancini. “It is a proof-of-principle study carried out as though we had a patient and a library of hormones. We tried to find the perfect hormone for the mutation through high-speed collection of dozens of measurements from thousands of cells.”
“In two of the three specimens we tested, we found we were able to reverse the activity of the mutated receptor to almost normal,” said Marcelli.
In one patient, large doses of the male hormone dihydrotestosterone were sufficient. In another, they used a synthetic androgen that also activated the receptor.
These approaches overcame the central problem – the mutation changes the shape of the receptor and prevents it from maintaining normal contact with the hormone. It is as though a key is bent and can no longer turn the tumblers in a lock. In these cases, the hormone is designed to go into a pocket created by the receptor. When the pocket is changed by the mutation, the hormone is unable to establish good contact.
“Large amounts of testosterone may create more stable contact,” said Marcelli. “The synthetic androgen may have a conformation that establishes better contact.”
Superandrogen
In the future, scientists may be able to screen large banks of such compounds to find a “superandrogen” that may be even more efficient.
“We might be able to use this technique to create a personalized medicine test,” said Mancini.
Similar techniques might be used to screen drugs for treatment of different cancers, particularly those in which the androgen receptor is responsible for cancer progression. This study proves that the concept is valid providing quantitative information collected quickly on numerous measurements normally requiring separate biochemical tests and huge numbers of cells.
Marcelli said they have yet to use this kind of technique in patients, and such studies will require careful preparation, and go through a variety of approvals before it can be used in clinics. He also said it would be used only in individuals with the partial form of the syndrome. Finding well-matched hormones to defective androgen receptors through screening of thousands of compounds from available libraries could be one of the future developments of this technique.
The paper’s first author, Dr. Adam T. Szafran, an M.D./Ph.D. student who worked in Mancini’s laboratory, championed these studies, said Mancini. Szafran is now finishing the clinical part of his studies at BCM.
Others who took part in this study include Drs. Sean Hartig and Ivan P. Uray, Maria Szwarc, Jennifer Bell, Huiying Sun, Yuqing Shen and Sanjay N. Mediwala, all of BCM. Sun, Shen and Mediwala are also of the MEDVAMC.
Funding for this work came from the National Institute of Diabetes and Digestive and Kidney Diseases, the John S. Dunn Foundation and the Veterans Administration.
Source: bcm.edu
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Forma Therapeutics raises $25.5M in Series B round
Last Updated on Saturday, 24 July 2010 04:09 Written by Editor Monday, 11 January 2010 06:15
Forma Therapeutics has closed on a Series B financing that raised a total of $25.5 million. The round was led by new investor Lilly Ventures. Lilly was joined by existing investors Novartis Option Fund and Bio*One Capital of Singapore. Lexington-based Cubist Pharmaceutical, Inc. also joined as a new equity investor through a conversion of a previously issued note.
Steve Hall, a venture partner at Lilly Ventures, will join Forma’s board of directors. The Cambridge-based company has a drug discovery technology platform designed to help develop new drug targets for cancer and other diseases.
“With this new funding, Forma will focus on advancing our internal target-based oncology programs and in parallel, we will continue to pursue non-dilutive collaborations to further build our integrated drug discovery platform,†said Steven Tregay, CEO of Forma, in a statement.
More about Forma Therapeutics
Forma, which was founded in May of 2007, first announced a $25 million dollar series A financing round in January of 2009, followed a week later by a $200 million deal with the Novartis Option Fund, which gave the company its first $4 million in funding to launch.
Also in January, Forma entered a three-year collaboration agreement with Cubist Pharmaceuticals Inc. in which Cubist developed antibacterial compounds discovered by Forma. The deal calls for Forma to receive $14 million in upfront payments, delivery and research funding and equity; If Cubist pursues commercialization of the compounds, the deal could garner Forma another $54 million in milestones and royalties.
In July, Forma formed partnerships with The Leukemia & Lymphoma Society to move the health agency’s research products toward development quickly, and with Novartis AG to use Forma’s cell-based screening platform to discover inhibitors for undisclosed protein-protein interaction targets to help develop cancer drugs.
Source: masshightech.com
JAX–West Helps Search for Compounds That Radically Extend Lifespan
Last Updated on Monday, 11 January 2010 05:30 Written by Editor Monday, 11 January 2010 05:30
In 2004, Avi Kremer, a 29-year old Harvard Business School student, was diagnosed with ALS. Avi’s doctors told him there was nothing that modern medicine could do for him. In response, he and fellow students founded Prize4Life, Inc. , a non-profit organization dedicated to accelerating research for treating and curing ALS by using the leverage of large inducement prizes. In 2006, Prize4Life opened the “ALS Biomarker Challenge,†offering a $1 million prize to a researcher who could find a biomarker that would reliably measure disease progress in ALS patients. A year ago, it established the “Avi Kremer ALS Treatment Prize,†a $1 million award for finding a treatment candidate that reliably and significantly increases the lifespan of ALS mouse models. Competing teams are actively pursuing several approaches, including therapies to replace damaged cells, protein-based therapeutics, and small molecule drugs that interfere with ALS-implicated pathways. Competition for both prizes is open to all interested researchers. Both prizes have attracted research teams from industry and academia from around the world.
The SOD1 Mouse
Three percent of ALS cases are associated with mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) gene, the first gene associated with ALS. With so little known about the genetics of ALS, research so far has concentrated on the pathogenesis of SOD1 mutations in laboratory mice. To provide researchers with the most widely used ALS mouse models available for preclinical drug testing, Prize4Life has partnered with The Jackson Laboratory (JAX). The models, popularly known as SOD1 mice, are distributed from dedicated supply colonies maintained by JAX® Breeding Services. JAX currently distributes 12 different SOD1 models – with different forms of the SOD1 mutation and on different genetic backgrounds. Among the most widely used of these models is JAX® Mice strain B6SJL-Tg(SOD1*G93A)1Gur/J (002726). Like several other SOD1 models, this one has a high copy number of the mutant human superoxide dismutase 1 (SOD1) transgene, which contains the Gly93–>Ala (G93A) substitution. The mutation underlies the most studied form of inherited ALS in humans. The mice lose motor neurons in the spinal cord, become paralyzed in one or more limbs, and die by four to five months. These phenotypes closely model those of human ALS (Gurney et al. 1994). As noted by Dr. Tom Maniatis, Chair of Columbia University’s Biochemistry & Molecular Biophysics Program, a prominent ALS researcher, and a member of Prize4Life’s Scientific Advisory Board, “An effective treatment for ALS is desperately needed, and the existing [SOD1] mouse model is the primary gateway to clinical trials†(CheckOrphan 2009).
SOD1 Mice Need Special Care
Many of the initial studies conducted with Tg(SOD1*G93A)1Gur/J mice have provided a wealth of information and insight on how to best use them in preclinical trials. However, like other highly expressed transgenes, the G93A transgene can spontaneously lose copy number, which can greatly confound experimental results. Therefore, the mice need to be handled carefully. When Prize4Life approached JAX to establish a dedicated supply for their researchers, Dr. Melanie Leitner (Chief Operating Officer and Chief Scientific Officer for Prize4Life), Dr. A. Sheila Menzies (Scientific Program Officer for Prize4Life), and Dr. Cathleen Lutz (Associate Director for Genetic Resource Science at JAX) produced a companion set of informational materials entitled “Working with ALS Miceâ€. The materials are available at www.jax.org/jaxmice/literature/factsheet/working_with_ALS_mice.pdf.
“Prize4Life spearheaded this effort,†say Lutz. “It’s really targeted to those investigators who are new to the field of ALS and who are working with the SOD1 mice and designing their preclinical trials. The scientific community has learned a great deal about how to work with these mice over the years. It’s important to make that information more widely known so that valuable time and resources aren’t wasted by repeating past mistakes.â€
If Prize4life succeeds in its goal of bridging the critical steps between academic discovery and therapy in the clinic, it could have major implications for ALS patients and for any group trying to solve a biomedical problem. Interested researchers can learn more at www.prize4life.org.
References
CheckOrphan. 2009. Prize4Life marks one-year anniversary of Avi Kremer ALS Treatment Prize. http://www.checkorphan.org/news/prize4life_marks_one_year_anniversary_avi_kremer_als_treatment_prize. October 13, 2009.
Gurney ME, Pu H, Chiu AY, Daly Canto MC, et al. 1994. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264:1772-5.
Source: animallab.com
Posted under Discoveries, Innovations and Patents, Drug Development, Press Releases, R & D | No Comments
DG-AMMOS: A New tool to generate 3D conformation of small molecules using Distance Geometry and Automated Molecular Mechanics Optimization for in silico Screening.
Last Updated on Monday, 11 January 2010 12:27 Written by Editor Monday, 11 January 2010 12:27
Discovery of new bioactive molecules that could enter drug discovery programs or that could serve as chemical probes is a very complex and costly endeavor. Structure-based and ligand-based in silico screening approaches are nowadays extensively used to complement experimental screening approaches in order to increase the effectiveness of the process and facilitating the screening of thousands or millions of small molecules against a biomolecular target.
Both in silico screening methods require as input a suitable chemical compound collection and most often the 3D structure of the small molecules has to be generated since compounds are usually delivered in 1D SMILES, CANSMILES or in 2D SDF formats.
Results: Here, we describe the new open source program DG-AMMOS which allows the generation of the 3D conformation of small molecules using Distance Geometry and their optimization via Automated Molecular Mechanics Optimization. The program is validated on the Astex dataset, the ChemBridge Diversity database and on a number of small molecules with known crystal structures extracted from the Cambridge Structural Database.
A comparison with the free program Balloon and the well-known commercial program Omega generating the 3D of small molecules is carried out. The results show that the new free program DG-AMMOS is a very efficient 3D structure generator engine.
Conclusions: DG-AMMOS provides fast, automated and reliable access to the generation of 3D conformation of small molecules and facilitates the preparation of a compound collection prior to high-throughput virtual screening computations.
The validation of DG-AMMOS on several different datasets proves that generated structures are generally of equal quality or sometimes better than structures obtained by other tested methods.
Author: David LagorceTania PenchevaBruno VilloutreixMaria Miteva
Credits/Source: BMC Chemical Biology 2009, 9:6
UT professor receives grant for new process
Last Updated on Wednesday, 16 December 2009 10:59 Written by Editor Wednesday, 16 December 2009 10:59
Using a pair of tweezers, a UT graduate student carefully lifted a nylon mesh square about the size of a thumbnail out of a small flask in his team’s lab.
The nylon had been soaking in a clear, watery solution containing a chemical compound — the “capture agent†— that it would bind with during a process tweaked by the student and his team.
Jennifer Brodbelt, a chemistry and biochemistry professor, received a $734,068 grant from the National Institutes of Health Oct. 1 to further develop the process — Desorption Electrospray Ionization (TM-DESI) — and perfect the nylon squares which isolate desired compounds from solutions.
Brodbelt, UT graduate students and two professors from Southwestern University in Georgetown were given a two-year deadline to gather blood from people of varying ages and levels of health, and to develop a more efficient method of analyzing the samples.
Results will be used to spot trends in the frequency of certain biological compounds, including amino acids.
A mass spectrometer, the machine Brodbelt’s team uses, can identify specific compounds in a mixture like blood. The tricky part was getting the sample to spray into the machine.
Joe Chipuk, a graduate student currently working on the project, was struck by the idea of having samples sprayed directly through a sifting material into the spectrometer.
Chipuk ran home and began collecting mesh materials to spray water through. He cut up his screen door, his wife’s tea strainer and the aerator from his kitchen faucet.
He went outside, used a hose to spray water through the mesh materials and observed the water’s exit path.
He then drafted a plan to create a mesh material soaked in a chemical that allows certain compounds to travel through but traps enough as to not let every metabolite escape.
After the unwanted materials are sorted out, the desired compounds attached to the mesh are released and analyzed by the spectrometer.
Before Chipuk’s square, the desorption process played out very much like a complicated billiards shot. The spray came down at an angle, hit the slide holding the blood sample and ricocheted off carrying the compounds through the spectrometer.
The new technique allows the compounds to be sorted and analyzed at a much faster pace than before. Chipuk said they can now analyze 50 samples in approximately eight minutes, whereas before, analyzing 50 samples would have taken more than 24 hours.
The team is focusing on improving the reliability and consistency of the mesh squares, Brodbelt said.
“The hope is that this could be a way to diagnose patterns of disease or determine a prognosis based on the pattern of metabolites,†Brodbelt said. “The sooner you have an idea that you might have cancer, or that you are on track to develop cancer, you could have screening done earlier and more frequently.â€
Source: dailytexanonline.com
Posted under Compound Screening, Discoveries, Innovations and Patents, Press Releases | No Comments
Tapeworm Drug May Hold Promise For Colon Cancer, Future Research
Last Updated on Tuesday, 15 December 2009 03:22 Written by Editor Tuesday, 15 December 2009 03:22
The findings about this compound, published in the Nov. 3 issue of Biochemistry journal, might prove valuable to patients and clinicians, who may benefit if there is a demonstrated boost to chemotherapy. Researchers also can use the compound to manipulate the receptor to learn more about a common cell replenishing pathway, called the Wnt pathway, which requires the receptor for normal activities and can go wrong in cancer cases.
The researchers had a choice: to screen libraries of several hundred thousand biochemical compounds or to use a library of about 1,200 FDA approved or biologically active compounds.
“We decided to take the less expensive route of screening FDA approved drugs, and fortunately, we found 26 compounds that seemed to meet our goal, but only one that truly worked with the Frizzled receptor,â€said Wei Chen, Ph.D., Assistant Professor of the Department of Medicine at Duke. “The goal was to drive the Frizzled 1 receptor from the outer membrane to the inside of the cell,†which effectively inactivated the receptor.
The effective compound, niclosamide, is currently approved for use against tapeworm infection. But some colon cancer patients, for example, have a Wnt pathway that is overactivated and may benefit from the “quieting†effects of niclosamide, which blocks the receptor in the Wnt pathway.
“The paper provides a rationale for clinicians to investigate using niclosamide for a new purpose,†Dr. Chen said. “Based on our findings, one oncologist at Duke is writing protocols for a phase 1 (safety) clinical trial to treat colon cancer patients with the intention of bringing our laboratory findings to the patient’s bedside.â€
Chen says he is proud of the work, which is “truly translational science.â€
“I am a basic scientist working with cell receptors, we have a medicinal chemist in our laboratory and one of our collaborators is Dr. H. Kim Lyerly, a professor of surgery, who is a researcher in gene- and immune-based therapies for cancer, as well as director of the Duke Comprehensive Cancer Center,†said Chen. “This type of diverse collaboration lets me shepherd a finding more rapidly from the laboratory to the clinic.â€
Provided by Duke University Medical Center
physorg.com
Scientists hope mouse research leads to new anti-cancer therapies
Last Updated on Wednesday, 2 December 2009 12:28 Written by Editor Wednesday, 2 December 2009 12:28
Recent collaborative work between Cambridge, Mass., research institutes has discovered a method of screening for chemicals that selectively kill breast cancer stem cells in culture and in mice, a breakthrough that may directly or indirectly lead to new anti-cancer therapies.
“One of the major difficulties with developing good anti-cancer drugs is that the anti-cancer drugs don’t cure the tumors, and part of the reason they don’t cure the tumors is that they’re not very effective in specifically attacking and eliminating the cancer stem cells,†said Dr. Robert Weinberg, founding member of the Cambridge-based Whitehead Institute and a biology professor at MIT. “We’re trying to develop techniques to understand what creates cancer stem cells and how they are perpetuated.â€
A theory prevalent amongst many researchers suggests that the aggressive subset of cancer cells — called cancer stem cells — drives tumor growth and causes tumors to regenerate after chemotherapy has killed 99 percent of their cells.
Isolating true-to-form cancer stem cells proved to be a challenge until recently, when researchers at Weinberg’s lab at the Whitehead Institute discovered a method to manipulate these cells.
The discovery allowed a team of scientists led by Dr. Piyush Gupta of the Cambridge-based Broad Institute to derive cell lines from human breast epithelial cells and use them to screen 16,000 chemicals in culture dishes. The scientists found that 32 of these chemicals specifically target cancer stem cells and kill them.
Gupta’s team then tested the chemical compounds in mice, and narrowed the results down to one chemical, salinomycin, that appeared to shrink tumor growth. The study was published in an August issue of the journal Cell.
“Ours was really the first step in a long process.†Gupta said. “We have one compound now, and it is not clear whether this one compound is ideal in terms of its activity and also in terms of its toxicity.â€
The discovery of the potent chemical does not necessarily mean that it will have any improvement over current cancer treatment. Gupta’s team has started the extensive follow-up testing that is necessary to determine in which stage eliminating cancer stem cells would be most beneficial to patients, and whether the compound is suitable for humans at all.
“Things sometimes appear very promising in pre-clinical studies but then in patients they may for whatever reason not work as well,†Gupta said. “All we can do is try to design the best possible preclinical studies in the hope that it will work in the patients. We really want to understand how the compounds work in animals before we even think about putting them in people.â€
Still, the new screening method is a promising development in the field of anti-cancer treatment. Gupta said he expects some cancer stem cell-targeting therapies to make into human trials within three to five years.
“For a while it seemed like these cancer stem cells were exciting, but there was very little known about them,†Gupta said. “Now I think that we’re finally at the stage where we can really start to understand what’s going on inside these cells.â€
Wicked Local Cambridge
Source: tauntongazette.com
PharmaGap Reports That GAP-107B8 Showed Strong and Consistent Anti-Cancer Activity in a Wide Range of Cancers in NCI Test
Last Updated on Wednesday, 2 December 2009 12:26 Written by Editor Wednesday, 2 December 2009 12:26
OTTAWA, ONTARIO, Oct 27, 2009 (MARKETWIRE via COMTEX) —-PharmaGap Inc. (TSX VENTURE: GAP)(OTCBB: PHRGF) (“PharmaGap” or “the Company”) is pleased to announce highly positive results from the United States National Cancer Institute (“NCI”) 5-dose in vitro anti-cancer screen of PharmaGap drug GAP-107B8. These results confirm and extend results announced in August from the single-dose study and provide definitive independent validation of GAP-107B8 as an active pharmaceutical ingredient against a wide range of cancers.
GAP-107B8 is a novel peptide protein kinase inhibitor that was designed to specifically target molecular signaling pathways in cancer cells. Targeted therapies are designed to target cancer cells while sparing surrounding normal, healthy, cells, thus causing less toxic effects than many standard chemotherapeutic agents currently in use.
Within a dose concentration range of 10 to 100 micromolar (u M), GAP-107B8 caused 100% growth inhibition (measured against cancer cell growth in untreated groups) in 51 of 56 cancer cell lines and caused at least 50% cancer cell death (measured against the number of cancer cells at the beginning of the test period) in 29 of 56 cancer cell lines.
The standard NCI test methodology generates three values that are used to measure the drug compound’s activity against the cancer cell-line panel. These are: the GI50, the dose that causes an average 50% growth inhibition in the cell lines; the TGI, the dose that causes an average 100% growth inhibition in the cell lines; and the LC50, the dose that causes an average 50% cell death in the cell lines. For GAP-107B8, the GI50 was determined to be 23 u M, the TGI was 51 u M, and the LC50 was 89 u M. These data provide a very clear range of focus for all future studies.
These results provided a large amount of data, from the NCI testing which will be used by the Company to select specific cancer types and to determine an optimum dosing range for future animal studies and subsequent clinical trials. Based on these and prior results, the Company will be focusing its immediate development program on ovarian cancer and melanoma. The first of these animal studies is currently underway at the Ottawa Hospital Research Institute (“OHRI”) in ovarian cancer. Further testing of GAP-107B8 on melanoma is about to commence under the guidance of Dr. Gary Schwartz at Memorial Sloan Kettering Cancer Center in New York. GAP-107B8 showed a strong effect in both melanoma and ovarian cancers in both single-dose and 5-dose testing at the NCI. In addition, the Company and NCI staff will meet in late November to discuss these results and ways in which the NCI may participate in various aspects of the development program for GAP-107B8.
The results across such a wide range of cancer cell lines, including a number which are known to be resistant to standard chemotherapy, indicate that GAP-107B8 has the potential to become a new cancer drug with less toxic side effects than common chemotherapeutic regimens.
Robert McInnis, President of the Company, stated “We are very pleased with the extent of activity in the NCI panel, as this activity against all cell lines provides a wide range of development opportunities for us, and provides us with additional support for a focus on ovarian cancer and melanoma. Our objective of the testing at the NCI – independent and verifiable validation of activity – has been fully realized. Over the past 12 months we have made significant progress in moving our lead drug to clinical trials: generating quality- controlled gram-scale production of the compound; achieving verifiable independent validation of compound activity at both the NCI and here in Ottawa at the OHRI; and programs underway in the area of bioassay development, understanding of signalling pathways involved, and continued testing programs at Memorial Sloan Kettering. This progress is very encouraging to me and to our team. Most importantly, results so far indicate a potential for new hope for the future of patients suffering from several types of cancer”.
About The National Cancer Institute
The National Cancer Institute (NCI), located in Bethesda, MD is an institute of the National Institutes of Health, the primary U.S. Federal Agency for conducting and supporting medical research. The NCI has a mandate to select and screen novel drug compounds that could potentially make a material difference in the “war against cancer”. Selection to the NCI screening program is through a competitive application process. Details on the NCI’s compound screening program can be found at http://dtp.nci.nih.gov/. More general information on the NCI is found at www.cancer.gov.
About PharmaGap Inc.
PharmaGap Inc. (TSX VENTURE: GAP)(OTCBB: PHRGF), based in Ottawa, ON, is a biotechnology company with a core focus on developing novel peptide therapeutics for the treatment of cancer. PharmaGap’s GAP-107B8 is a novel peptide drug designed to inhibit the activity of protein kinase C (PKC), a cell signalling enzyme implicated in certain types and stages of cancer. Independent peer-reviewed research has demonstrated that over-expression of PKC plays a role in the development of many cancer types. For more information please visit www.pharmagap.com.
Note: Neither the TSX Venture Exchange nor its Regulation Services Provider (as that term is defined in the policies of the TSX Venture Exchange) accepts responsibility for the adequacy or accuracy of this release. No Securities Commission or other regulatory authority having jurisdiction over PharmaGap has approved or disapproved of the information contained herein. This release contains forward looking statements that may not occur or may change materially.
Contacts: PharmaGap Inc. Robert McInnis President & CEO 613-990-9551 bmcinnis@pharmagap.com www.pharmagap.com
SOURCE: PharmaGap Inc.
Aeolus Drug Protects the Gastrointestinal Tract in Acute Radiation Syndrome Studies Sponsored by the National Institutes of Health`s National Institute for Allergy and Infectious Diseases
Last Updated on Wednesday, 2 December 2009 12:12 Written by Editor Wednesday, 2 December 2009 12:12
* AEOL 10150 Effectively Increases Regeneration of GI Stem Cells and Reduces the
Severity and Duration of Diarrhea
* Drug Improves Survival When Administered 24 Hours after Total Body
Irradiation
MISSION VIEJO, Calif.--(Business Wire)--
Aeolus Pharmaceuticals, Inc. (OTCBB: AOLS) announced today that recent
experiments in preclinical models conducted by the National Institutes of
Health`s (NIH), National Institute of Allergy and Infectious Diseases (NIAID)
Radiation/Nuclear Medical Countermeasure Development program have shown that
AEOL 10150 can effectively increase regeneration of gastro-intestinal (GI) stem
cells, reduce the severity and duration of diarrhea and improve survival when
administered at 24 hours after doses of total-body irradiation that produce the
lethal GI syndrome. There are no published studies of agents that accomplish
this enhanced stem cell regenerative effect while maintaining GI function and
improving survival when administered post irradiation.
"The Aeolus drug AEOL 10150 passed our first phase of rigorous testing and
showed definitive effects on crypt stem cells and other secondary parameters
used to assess drug efficacy in ameliorating the acute GI syndrome," stated
Catherine Booth, Ph.D., Managing Director, Contract Research Services at
Epistem, Ltd. "This is one of few drugs shown to affect 'both' stem cell crypt
regeneration and survival in a syndrome that heretofore has been resistant to
mitigation with drugs administered at 24 hours post lethal exposure."
NIAID has a contract with the University of Maryland to provide product
development support services for the development of countermeasures against
radiation exposure. These studies are being conducted by Epistem, a
subcontractor of the University of Maryland, in compliance with criteria of the
FDA that are a pre-requisite for movement of the Aeolus drug along the pathway
for FDA licensure to treat lethally irradiated persons in the event of a
terrorist nuclear act. Epistem operates a major contract research organization
and provides services to identify novel drugs that can protect or improve the
repair of the gastrointestinal (GI) tract following exposure to irradiation and
performed these studies as part of its US NIH`s program for the screening of a
novel agents for bio-defense applications.
The NIH NIAID Radiation/Nuclear Medical Countermeasure Development program leads
the U.S. effort to develop treatments for radiation sickness following a nuclear
terrorist attack. GI-ARS is a massive, currently untreatable, problem following
high-dose, potentially lethal radiation exposure. Agents that mitigate these
effects would reduce sickness and hopefully prevent fatalities. The tests
performed by NIH/NIAID are also likely to identify agents with oncology
supportive care applications - agents that will reduce the severe ulceration and
diarrhea (mucositis) experienced by patients during radio- and chemo-therapy.
Risk of injury to the intestine is dose-limiting during abdominal and pelvic
radiation therapy-interventions that limit post-irradiation intestinal
dysfunction would have significant impact in large number of patients, estimated
to be between 1.5 to 2 million cancer survivors with post-irradiation intestinal
dysfunction. AEOL 10150 has previously demonstrated protective effects in
protecting healthy normal cells from damage occurring due to cancer radiation
therapy in preclinical models.
Radiation Damage to the GI Tract
The intestinal epithelium, a single layer of cells lining the surface of the GI
lumen, is responsible for vital functions of nutrient absorption, maintaining
fluid and electrolyte balance and protection of the body from bacteria,
bacterial toxins and non absorbed materials. The functional integrity of the GI
system is maintained via incessant production of epithelial cells from
specialized stem cells located in crypts at the base of the epithelium.
High-dose, total-body irradiation can result in a lethal GI syndrome that
results in significant morbidity and mortality within days consequent to killing
of the crypt stem cells and loss of the protective and absorptive epithelial
barrier. There are no FDA-approved drugs or biologics to treat the acute GI
syndrome.
About AEOL 10150
AEOL 10150 is a small molecule that catalytically consumes reactive oxygen and
nitrogen species (free radicals). The compound is a manganoporphyrin that
contains a positively-charged manganese metal ion that is able to accept and
give electrons to and from reactive oxygen species ("ROS") and reactive nitrogen
species ("RNS"). Research has shown that ROS and RNS have important cell
signaling roles, and through its interaction with RNS and ROS, AEOL 10150
appears to have multiple mechanisms of action including anti-oxidant,
anti-inflammatory and anti-angiogenic activities. In preclinical studies AEOL
10150 has demonstrated reductions in the markers for tissue hypoxia,
angiogenesis, inflammation and oxidative stress. Specifically, AEOL 10150 is
able to down-regulate oxidative stress and severe inflammation, which is
responsible for much of the tissue destruction that occurs as a result of
radiation exposure.
AEOL 10150 offers several unique advantages as a countermeasure for the
treatment of ARS, mustard gas and chlorine gas for civilian and military
populations. These include:
-- Flexible Treatment Paradigm - AEOL 10150 is intended for the treatment of
patients post-exposure, even in those who are already exhibiting symptoms,
eliminating the need for immediate administration in a predefined treatment
window. This approach has the added benefit of not requiring biodosimetry (a
means of laboratory analysis of the blood to determine the level of radiation
exposure).
-- Advanced Development Stage - AEOL 10150 has demonstrated safety in three
human clinical trials, and has an extensive pre-clinical safety and toxicology
package completed. The product also has an established stability profile that
permits long-term storage.
-- Large scale manufacturing - Aeolus has contract capacity with a large
manufacturing site to mass produce large quantities of AEOL 10150 under GMP
conditions.
-- Multiple Applications - AEOL 10150 has demonstrated protective effects
against radiation and mustard gas exposure, and within these indications has
shown the ability to treat multiple organ systems.
-- Commercial Application - Additionally, AEOL 10150 is being developed for use
as an adjunct to cancer radiation therapy, and preclinical data suggest that the
compound protects healthy normal cells from the effects of radiation without
compromising the efficacy of the radiation in killing tumor cells.
Potential for AEOL 10150 as a Countermeasure Against Multiple Terrorist Threats
AEOL 10150 has shown significant protective effects against radiation and
mustard gas in preclinical models. Additionally, based on its mechanism, it is
believed that the compound may potentially protect against exposure to chlorine
gas. Studies have been initiated to further explore AEOL 10150`s ability to
protect the lungs from damage due to exposure to mustard gas and chlorine gas. A
compound with the potential to protect against multiple threats would be of
significant benefit in both the military and civilian efforts to protect
citizens against potential threats. The FDA has a special rule under which
compounds may be approved for use against chemical and nuclear threats on the
strength of preclinical efficacy studies, which allows the potential for an
accelerated approval path versus conventional pharmaceutical applications.
About Aeolus Pharmaceuticals
Aeolus is developing a variety of therapeutic agents based on its proprietary
small molecule catalytic antioxidants, with AEOL 10150 being the first to enter
human clinical evaluation. AEOL 10150 is a patented, small molecule catalytic
antioxidant that mimics and thereby amplifies the body`s natural enzymatic
systems for eliminating reactive oxygen species, or free radicals. Studies
funded by the National Institutes for Health are currently underway evaluating
AEOL 10150 as a treatment for exposure to radiation, mustard gas and chlorine
gas. Additionally, the Company has funded mouse and non-human primate studies
necessary to seek approval of the compound as a treatment to protect and/or
mitigate radiation-induced damage to the lungs for which there are no
FDA-approved drugs. Radiation-induced pneumonits and/or fibrosis are potentially
lethal delayed effects of acute radiation exposure. The ability to control these
delayed consequences will also translate into the clinic and further emphasize
the dual utility of AEOL 10150.
About Epistem, Ltd.
Epistem is a biotechnology company commercializing its expertise in epithelial
stem cells in the areas of oncology, gastrointestinal diseases and
dermatological applications. Epistem develops innovative therapeutics and
biomarkers and provides contract research services to drug development
companies. The Group`s expertise is focused on the regulation of adult stem
cells located in epithelial tissue, which includes the gastrointestinal tract,
skin, hair follicles, breast and prostate. Epistem does not conduct research in
the areas of embryonic stem cells or stem cell transplantation. Epistem operates
three distinct business divisions, Contract Research Services, Novel Therapies
and Biomarkers.
Epistem`s Contract Research Services division provides scientific expertise and
preclinical research models to the NIH`s research programme on Radiation/Nuclear
Medical Countermeasure Development. This research programme, funded by the
National Institute of Allergy and Infectious Diseases through a contract with
the University of Maryland School of Medicine, tests drugs from early screening
through advanced development for the prevention and treatment of radiation
sickness following exposure to high dose radiation following a nuclear terrorist
attack. Epistem has developed its proprietary models to provide a unique insight
into the mechanisms of intestinal damage and repair following radiation
exposure. Epistem`s models evaluate the efficacy, mechanism of action, optimal
drug dosing and scheduling of potential new treatments. Epistem has an
eight-year track record of providing testing services to over 130 international
company clients in the United States, Europe, and Japan.
The statements in this press release that are not purely statements of
historical fact are forward-looking statements. Such statements include, but are
not limited to, those relating to Aeolus` product candidates, as well as its
proprietary technologies and research programs. Such forward-looking statements
involve known and unknown risks, uncertainties and other factors that may cause
Aeolus` actual results to be materially different from historical results or
from any results expressed or implied by such forward-looking statements.
Important factors that could cause results to differ include risks associated
with uncertainties of progress and timing of clinical trials, scientific
research and product development activities, difficulties or delays in
development, testing, obtaining regulatory approval, the need to obtain funding
for pre-clinical and clinical trials and operations, the scope and validity of
intellectual property protection for Aeolus` product candidates, proprietary
technologies and their uses, and competition from other biopharmaceutical
companies. Certain of these factors and others are more fully described in
Aeolus` filings with the Securities and Exchange Commission, including, but not
limited to, Aeolus` Annual Report on Form 10-K for the year ended September 30,
2008. Readers are cautioned not to place undue reliance on these forward-looking
statements, which speak only as of the date hereof.
Aeolus Pharmaceuticals, Inc.
John L. McManus
President and Chief Executive Officer
1-949-481-9825
Source: reuters.com
Copyright Business Wire 2009
Researchers find candidates for new HIV drugs
Last Updated on Tuesday, 1 December 2009 11:26 Written by Editor Tuesday, 1 December 2009 11:26
While studying an HIV protein that plays an essential role in AIDS progression, researchers at the University of Pittsburgh School of Medicine have discovered compounds that show promise as novel treatments for the disease.
HIV drug discovery efforts have met with little success in finding compounds that interact with an important HIV virulence factor, called Nef, because it lacks biochemical activity that can be directly measured, explained Thomas E. Smithgall, Ph.D., William S. McEllroy Professor and Chair, Department of Microbiology and Molecular Genetics, and senior author of the paper, which was published last week in the early, online version of ACS Chemical Biology.
To get around that problem, Dr. Smithgall’s team developed an assay to measure Nef function indirectly by coupling it to another protein, called Hck, which Nef activates in HIV-infected cells. Because Hck activity can be easily measured, the investigators were able to use it as a reporter for Nef activity in an automated high-throughput screening process. In collaboration with the University of Pittsburgh Drug Discovery Institute, they screened a library of 10,000 chemical compounds against the coupled proteins to see which ones influenced Nef-induced activation of Hck.
After further testing, they confirmed that three compounds inhibited the activity of the Nef-Hck complex and, more importantly, all of them also interfered with HIV replication. One compound was so effective that it suppressed HIV replication to undetectable levels in cell culture experiments.
“So we now have a way to rapidly and efficiently screen for inhibitors of Nef signaling through Hck,” Dr. Smithgall said. “But the surprise was that some of those inhibitors also showed strong antiviral activity in cell culture models.”
There is evidence that people infected with HIV variants that have mutations in the Nef gene take substantially longer to develop disease symptoms or AIDS, he said. In animal models, disrupting the production of Nef from the virus or its interaction with Hck also delays or prevents disease symptoms. The next challenge for the researchers will be to determine whether these compounds also interfere with progression of AIDS-like disease in animal models by blocking Nef function.
“Most current therapies for HIV infection use drugs that interfere with the function of viral enzymes such as reverse transcriptase or with the interaction of the virus and the host cell,” Dr. Smithgall said. “Targeting Nef represents an entirely new approach that could be useful to deal with issues such as drug-resistant HIV strains, and may slow the progression to AIDS.”
He added that Nef is just one of several so-called “accessory proteins” encoded by HIV which are important virulence factors in AIDS. Inhibitory compounds against some of the others might be revealed using a similar coupled protein approach for high throughput screening.
Source: labspaces.net
Scientists get closer to making safe patient-specific stem cells
Last Updated on Monday, 30 November 2009 01:55 Written by Editor Monday, 30 November 2009 01:55
Scientists are a big step closer to their long-term of goal of creating patient-specific stem cells that are safe to use and don’t require the destruction of embryos.
Induced pluripotent stem cells – also known as iPS cells – are all the rage in the nascent field of regenerative medicine. Like embryonic stem cells, they have the potential to become any type of cell in the body and could be used to grow replacement parts, such as insulin-producing beta cells for diabetes patients or nerve cells for repairing spinal cord injuries.
Even better, they can be made by reprogramming skin or other cells from the patients who need them. That not only eliminates the need to use embryos, it ensures that the replacement tissues made from iPS cells are genetically matched to patients and won’t be rejected by the body’s immune system.
But there’s still a big catch: In order to rewind adult cells to a pluripotent state, researchers have to turn on a set of dormant genes that have the potential to cause tumors. So do the viruses they use to activate those genes.
So researchers have been looking for ways around this problem. One approach is to snip out the genes and viruses once the reprogramming is complete. Another is to use DNA sequences called transposons in place of viruses, then delete the transposons after they’re no longer needed. One group of researchers has even used genetic engineering to modify the key genes so that they can enter the skin cells without requiring viruses or transposons.
But many scientists think the safest approach is to replace the genes altogether with so-called small molecules. In a study published online today in the journal Cell Stem Cell, researchers from the Harvard Stem Cell Institute report that a single compound they dubbed RepSox can replace two of the four key reprogramming genes.
“We’re halfway home, and remarkably we got halfway home with just one chemical,†senior author Kevin Eggan, a professor in Harvard’s department of stem cell and regenerative biology, said in a statement.
Eggan’s team identified RepSox by screening 200 compounds and waiting a couple of weeks to see which of them did the best job of transforming mouse cells into iPS cells in combination with three of the four reprogramming genes. The researchers were surprised to find that their compound not only replaced the gene Sox2 (hence the name RepSox), but also made the gene c-Myc obsolete.
Now the group will turn its attention to finding other small molecules that could replace the remaining genes – Oct4 and Klf4 – as well, “opening a route to purely chemical programming,†they write.
Scripps Research scientists awarded $3.9 million grant to develop new compound screening platform
Last Updated on Tuesday, 20 October 2009 10:04 Written by Editor Tuesday, 20 October 2009 10:04
Bicoastal effort could help revolutionize the search for new therapies
La Jolla, CA, and Jupiter, FL, October 5, 2009 –A pair of scientists from The Scripps Research Institute, one on each coast, has been awarded a five-year $3.9 million grant from the National Institutes of Health (NIH) to develop a new technology to accelerate the search for new protein ligands – compounds that bind to proteins and alter their function.
Current screening technology, which is slow and expensive, has caused what the NIH calls a “major bottleneck” in the search for these basic tools that are key for the broader study of biological processes and that lay the groundwork for development of most drugs.
The grant, awarded as part of the NIH’s new Roadmap Transformative R01 Program, will be shared between the laboratories of Tom Kodadek, Ph.D., a professor in the Scripps Research Departments of Chemistry and Cancer Biology in Jupiter, Florida, and Benjamin Cravatt III, Ph.D., professor and chair of the Department of Chemical Physiology and member of The Skaggs Institute for Chemical Biology and Helen L. Dorris Child and Adolescent Neuro-Psychiatric Disorder Institute at Scripps Research in La Jolla, California.
“Ben and I are extremely pleased to win this highly competitive award and to be among the first selected for the new Transformative Grant program from the NIH,” Kodadek said. “This is a perfect example of the tremendous collaborative possibilities available within Scripps Research. We worked on the proposal together and the fact that we’re both part of the same national institution will make the work that much easier as we move ahead.”
Cravatt added, “This project is a good reflection of what those of us at Scripps Research in La Jolla and in Florida are trying to accomplish – fostering collaborative interaction and working on complimentary research projects. This will help cement the strong working relationship between our two campuses.”
The NIH Roadmap Transformative R01 (T-R01) Program awards were launched this year to support exceptionally innovative, high risk, original, and/or unconventional research projects that have the potential to create or overturn fundamental scientific paradigms.
“The appeal of the Pioneer, New Innovator, and now the T-R01 programs, is that investigators are encouraged to challenge the status quo with innovative ideas, while being given the necessary resources to test them,” said NIH Director Francis S. Collins, M.D., Ph.D. “The fact that we continue to receive such strong proposals for funding through the programs reflects the wealth of creative ideas in science today.”
Two Innovative Methods and a Cab Ride
The new Scripps Research project will combine two separate technologies from each laboratory – a peptoid library synthesis and screening platform developed in the Kodadek laboratory and an activity-based protein profiling system developed in the Cravatt laboratory.
Kodadek’s screening platform involves the creation of vast libraries of peptoids (peptoids are synthetic molecules that are similar to peptides, compounds that when joined together make up proteins) displayed on microscopic beads that are screened against fluorescently tagged proteins that light up after binding with a high affinity, highly selective ligand.
“Our screening technology simulates the cellular environment,” Kodadek said, “because the tagged proteins, which represent only a small fraction of the total, are mixed in with un-tagged competitors. There is a specificity filter built into the process from the beginning.”
The Cravatt Laboratory has pioneered the Activity-Based Protein Profiling technology, which allows scientists to identify protein classes based on their activity. The basic technology attaches a single label or probe to proteins from a particular subset of the proteome, which allows access to what are considered low abundance proteins and makes it ideal for massive parallel screening experiments. So far, Activity-Based Protein Profiling probes have been developed for more than a dozen distinct enzyme classes.
Cravatt’s technology makes it possible to target what he calls “interesting classes of proteins” but in a highly parallel fashion – hundreds of screens at a time of those multi- million member peptoid libraries. Although both scientists have known one another for some time, many of the details of the collaboration were worked out on a cab ride from England’s Heathrow airport to London last summer.
“Tom and I had an editorial board meeting in London, and shared a cab from the airport,” Cravatt said. “The fact that Tom had recently joined Scripps Florida helped get us energized about the project.”
“It’s true,” Kodadek added. “The ideas behind the grant proposal just popped out of that ride.”
A Transformational Marriage
The combination of the Kodadek and Cravatt advanced technologies will allow the screening of massive peptoid libraries (1-10 million synthetic compounds) in parallel fashion, a novel strategy that the scientists predict will increase the rate of ligand discovery by several hundred times over current methods.
“The gist of our proposal is quite simply marrying these two beautifully worked out technologies,” Kodadek said. “We have a good track record on both sides, plus we’re building off these innovative platforms, so if this works, and I’m certain it will, it will definitely be transformational.”
That transformation, when it comes, should result in more lead drug candidates, Kodadek said, because while the scientists’ success rate has been lower than those using current high throughput screening technology, the quality of the ligands identified has been significantly better. Some of this is due to the fact that simple synthetic compounds like peptoids have many advantages over other ligands such as antibodies. They can be modified easily for attachment to surfaces and can be produced in relatively large amounts at lower cost and rather quickly – a multi-million member peptoid library, for example, can be created in around three days.
“The way most science works today,” Cravatt said, “is that researchers tend to huddle around those areas where there are tools available. By combining our technologies, we will have a streamlined, unbiased way to identify high quality protein ligands and that will give us access to a large part of the proteome that others can’t study right now because the current technology is inadequate.”
About The Scripps Research Institute
The Scripps Research Institute is one of the world’s largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter, Florida.
Source: eurekalert.org
AIDS Study Flushes Out Hidden Virus, Pointing to Possible Cure
Last Updated on Wednesday, 14 October 2009 10:02 Written by Editor Wednesday, 14 October 2009 10:02
Oct. 2 (Bloomberg) — Scientists, moving closer to a cure for AIDS, identified a way to find medicines that would help rid patients of the hardest-to-treat pockets of HIV.
Current anti-HIV drugs reduce the virus to undetectable levels without eradicating it. The virus survives by lying dormant in immune-system cells, where the medicines don’t reach them. Scientists from Johns Hopkins University and the Howard Hughes Medical Institute reported yesterday that they developed a way of luring out these cells in laboratory experiments, an achievement they said may lead to a cure if repeated in humans.
In 2007, about 2.7 million people were newly infected with HIV, the virus that causes AIDS, and 2 million died of the disease, making it the world’s deadliest infectious malady, according to the Geneva-based World Health Organization, an arm of the United Nations. Scientists looking to stop HIV have turned to attacking so-called latent reservoirs of the virus after efforts to prevent infection, such as vaccines and gels, largely failed.
“This is a way in which you could envision finding a drug that would, in conjunction with existing treatment, allow us to cure patients,†said Robert Siliciano, the professor who led the study at Johns Hopkins’s medical school in Baltimore. More research is needed, he said.
For about 12 years, doctors have known that HIV, or human immunodeficiency virus, can lie dormant in immune-system cells called resting CD4s found in the lymph nodes, spleen and blood. There the virus stops replicating, avoiding the drugs designed to kill it.
Roaring Back
Studies have shown latent HIV comes roaring back when treatment is interrupted, condemning patients to a lifetime on drugs such as Abbott Laboratories’ Kaletra that can cause side effects including nausea, liver damage and fat buildup. Eliminating the last vestiges of the virus could cure patients of the disease, allowing them to stop treatment.
Siliciano’s team mimicked HIV latency in a lab dish using a gene called Bcl-2 to turn normal CD4s into resting cells capable of hosting the dormant form of HIV.
The researchers used the model to test 2,400 chemicals, finding 17 that coaxed the virus out of hiding, kick-starting its normal process of replication. In a human, that would make the virus susceptible to drugs. The best performer was a compound called 5HN found in the leaves, bark and roots of the black walnut tree.
‘Key Thing’
“They’ve found a way to find drugs — that’s the key thing,†said Stephen Kent, a professor of immunology at the University of Melbourne, in a telephone interview yesterday. “We’ve really just been guessing up to this point about ways to get at this. Having a system for screening drugs is a big advance over what we’ve had so far.â€
The result was achieved without rousing non-infected CD4 cells, avoiding a potentially fatal scenario called a cytokine storm in which the body’s immune system overreacts.
The study has limitations, Siliciano said. First, 5HN may be too toxic for use in humans, he said by phone.
“It’s going to require additional research to find something that does the same thing but doesn’t have lots of other effects,†Siliciano said. “We’re pretty confident that we’ll find lots of compounds that work, but whether any of those will be sufficiently free of other effects — that’s not clear,†he said.
Second, recent studies have pointed to another reservoir of latent HIV that has yet to be identified, Siliciano said.
No Test
“We may have to find another drug to target that reservoir,†he said. “First we have to identify what it is.â€
There’s no test for identifying whether a patient has latent HIV, meaning the only way to be sure a drug has polished off the virus is to cease treatment and see if it returns, the University of Melbourne’s Kent said.
The findings are an advance that may allow researchers to come up with a drug they could start testing in humans, Kent said.
“To get something like that into clinical trials is only a few short years — it’s not decades,†he said. “Then it’s got to work.â€
The study was published yesterday in the Journal of Clinical Investigation, a peer-reviewed journal published by the American Society for Clinical Investigation, of Ann Arbor, Michigan.
The research was funded by the National Institutes of Health in Bethesda, Maryland; the Doris Duke Charitable Foundation in New York; and the Howard Hughes Medical Institute in Chevy Chase, Maryland.
To contact the reporter on this story: Simeon Bennett in Singapore at sbennett9@bloomberg.net
Source: bloomberg.com
Posted under Discoveries, Innovations and Patents, HIV Research, New Drugs, Press Releases | No Comments
GENFIT identifies compounds which modulate clock genes for the treatment of cardiometabolic disease and CNS disorders
Last Updated on Monday, 12 October 2009 02:29 Written by Editor Monday, 12 October 2009 02:29
Lille (France), Cambridge (Massachusetts, United States), September 28, 2009 – GENFIT (Alternext: ALGFT; ISIN: FR0004163111), a biopharmaceutical company at the forefront of drug discovery and development, focusing on the early diagnosis and preventive treatment of cardiometabolic and neurodegenerative diseases, today announces the successful identification of Hit compounds for an orphan nuclear receptor which plays a key role in the regulation of circadian cycle in different organs. These Hits were identified through the screening of chemical libraries performed at GENFIT facilities in Lille.
In humans, many aspects of behavior and physiology are coordinated by an endogenous circadian rhythm (circa diem, meaning approximately one day) that is generated by an internal clock system which synchronizes daily variations in gene expression to rhythms such as sleep and wake alternance, variations in body temperature, blood pressure, heart rate, as well as cognition, attention and mood.
A large body of evidence from both human and animal studies now points to a relationship between circadian disorders and altered metabolic response, suggesting that circadian and metabolic regulatory networks are tightly interconnected.
As a consequence, misalignment of the internal timing system versus environmental stimuli, such as day/night cues, as experienced during jetlag or shift work, may result in dysregulation of physiological cycles of fuel utilization and energy storage, and has been associated with increased risk to develop obesity, type 2 diabetes, hyperlipidemia, high blood pressure and cardiovascular disease. As well, modulating, resetting and stabilization of central circadian rhythms have been proposed as therapeutic strategies for certain CNS disorders.
“This is an important milestone in our drug discovery programs in the field of cardiometabolic disease and CNS disorders”, says Dean Hum (CSO of Genfit). “Deorphanisation of this nuclear receptor further demonstrates our expertise in this class of therapeutic targets, and provides novel series of compounds to address the focus therapeutic areas of Genfit with a very innovative approach via modulation of clock genes and the circadian rhythm”.
About GENFIT:
GENFIT is a biopharmaceutical company focused on the Discovery and Development of drug candidates in strategic therapeutic fields linked to cardiometabolic and neurodegenerative disorders (prediabetes/diabetes, atherosclerosis, dyslipidemia, obesity, Alzheimer’s…). GENFIT uses a multi-pronged approach based on early diagnosis, preventive solutions, and therapeutic treatments to address these major public health concerns and their unmet medical needs. GENFIT’s proprietary research programs and its partnerships with leading pharmaceutical companies, including Sanofi-Aventis, Solvay Group, Pierre Fabre, and Servier, have resulted in the creation of a rich and diversified pipeline of drug candidates at different stages of development. GENFIT’s lead proprietary compound, GFT505, is currently in Phase II and two other compounds, in partnership with Sanofi-Aventis (AVE0897) and SOLVAY (SLV341), are in the advanced stages of Phase I.
With facilities in Lille, France, and Cambridge, MA (USA), the Company has about 130 employees, including over 100 scientists. GENFIT is a public company listed on the Alternext trading market by Euronext(TM) Paris (Alternext: ALGFT; ISIN: FR0004163111). www.genfit.com
Contacts:
GENFIT
Jean-Fran̤ois Mouney РChairman of the Management Board
+33 (0)3 20 16 40 00
Milestones – Press Relations
Bruno Arabian
+33 (0)1 75 44 87 40 / +33 (0)6 87 88 47 26 – barabian@milestones.fr
Copyright Hugin
The appendixes relating to the press release are available on:
http://www.hugingroup.com/documents_ir/PJ/CO/2009/158601_88_7960_20090928-PR-GENFIT.pdf
This announcement is originally distributed by Hugin. The issuer is solely responsible for the content of this announcement.
Source: euronext.com
Novel two-step chemical process makes cancer cells glow quickly, safely
Last Updated on Monday, 12 October 2009 12:39 Written by Editor Monday, 12 October 2009 12:39
WASHINGTON – Researchers at Massachusetts General Hospital have developed a two-step process that uses a chemical reaction to make live cancer cells light up quickly and safely.
This attains significance because scientists generally label cells with coloured or glowing chemicals to observe how basic cellular activities differ between healthy and cancerous cells, but existing techniques are either too slow or too toxic to perform on live cells.
Under the novel process, chemically modified antibodies first home in on cancer cells, and then a chemical reaction called cycloaddition transfers a dye onto the antibody making the cancer cells glow when viewed through a microscope.
Philip Dawson, a member of Faculty of 1000 Biology and leading authority in chemistry and cell biology, reviewed a study and observed that the novel cycloaddition reaction is fast, very specific, and requires minimal manipulation of the cells.
He comments that, in combining antibody binding with the cycloaddition, “low signal-to-noise ratios are achievedâ€.
He points out that the new labelling technique could be used to track the location and activity of anti-cancer drugs, the location of cancer-specific proteins within the cell, or to visualize cancer cells inside a living organism.
Dawson concludes that cycloaddition will allow scientists to observe live cancer cells in the body, leading to a better understanding of cancer’s basic processes. (ANI)
Source: http://blog.taragana.com
Sirona Biochem Says SGLT Test Results Confirm Key ‘Breakthrough’
Last Updated on Friday, 9 October 2009 12:02 Written by Editor Friday, 9 October 2009 12:02
Sirona Biochem Corp. (TSX-V: SBM), an emerging biotech company focused on diabetes and obesity, says results of testing its unique SGLT inhibitor molecules demonstrate a key breakthrough milestone for Sirona Biochem.
Sirona Biochem CEO, Dr. Howard Verrico, said, “There are two vital steps in the early stage of drug testing: validation of concept i.e. a molecule is able to hit the desired target and secondly its in vivo effectiveness. This first round of testing has shown a key breakthrough milestone in the process of validating this concept.”
“The test results now mean we can proceed to find out whether the molecules are selective, safe and robust enough to have potential to be effective when they reach the parts of the body where the re-uptake of glucose needs to be limited.”
Dr. Bertrand Plouvier, Chief Scientist, said, “The results from the first round of screening are indeed very encouraging and Sirona Biochem will use the next following months to further study the molecules through specific assays to demonstrate their effectiveness and drug likeness.”
Dr. Verrico said management of sugar metabolism is a primary medical challenge associated with treating diabetes and obesity and that is why SGLT inhibitors show such promise in this regard. “At present SGLT2 inhibitors have demonstrated their ability to limit the re-uptake of glucose back into the blood stream from urine. However, they have been notoriously lacking in ability to resist being rapidly metabolized by the body, thus rendering them largely ineffective.
“What we have now done is show that our molecules, with their unique GlycoMim® technology, can inhibit the glucose transporter SGLT2. The next challenge, and an exciting one, is to show that our molecules are selective, safe and have the potential to have an increased efficacy compared to the current molecules undergoing clinical development.”
Sirona Biochem owns the worldwide product rights to a library of unique sodium glucose transporter (SGLT) inhibitors to treat diabetes and obesity. SGLT inhibitors, as previously stated, block the re-uptake of excess sugars from urine, which can then reduce high blood sugar towards normal levels.
Sirona Biochem has entered into a strategic partnership with TFChem, a drug discovery company based in Rouen, France. TFChem licenses its technology of fluorinated carbohydrate mimics: GlycoMim®, and products in development to biotech companies. This strategic partnership was completed by a detailed research and licence agreement signed on September 29, 2008.
23.6 million people, or 7.8% of the population of the United States, have diabetes. (February 2009 DACG.ORG)
Market Trends
In 2007, the prevention and treatment of diabetes and its complications was estimated to cost US$ 232 billion according to the International Diabetes Federation. By 2025, this is likely to increase to more than US$ 302.5 billion.
The diabetes drug market reached US$18 billion in 2005, and is expected to increase to $21-25 billion in 2011. With many new products yet to realise their full potential and the high incidence of T2DM expected in emerging markets, prospects for the sector look strong. Some of the fastest growing markets for diabetes are in emerging economies. India, China and Indonesia are in the top 5 for disease prevalence. The impact for both branded and generic drugs is considerable.
Furthermore, in recent years, obesity has become a major health problem for many post-industrial societies, so much so that in 2004, the United States Health and Human Services declared obesity to be a disease. The World Health Organization (WHO) projects that globally in 2005, 1.6 billion adults were overweight with at least 400 million adults obese. By 2015, approximately 2.3 billion adults will be overweight and 700 million will be obese. Obesity poses a major health risk because it greatly increases the risk of co-morbidities such as diabetes, cardiovascular diseases, arthritis, and cancer. Recognizing the potential for a new blockbuster market, major pharmaceutical companies have increasingly focused on obesity and its causes and, in the process, seeking to identify many potential targets and pathways that could be exploited to create novel therapies.
Sirona Biochem’s website is at: www.sironabiochem.com where we feature the most recent information about the company and its activities. Alternatively, investors are able to e-mail all questions and correspondence to info@sironabiochem.com where they can also request to be added to the investor e-mail list to receive all future press releases and updates or call John Dougherty, Corporate Development at 604-641-4466.
About Sirona Biochem
Sirona Biochem Corp. (TSX-V: SBM) is an emerging biotech company dedicated to the discovery and development of novel drug compounds. The current focus is on treatments for Type II diabetes and obesity. Sirona has entered into a license agreement with TFChem S.A.R.L., a drug discovery company based in Rouen, France. TFChem licenses its technology of fluorinated carbohydrate mimics: GlycoMim®, and products in development to biotech companies. The license agreement with TFChem provides for research and development of new compounds known as SGLT Inhibitors. SGLT inhibitors are a new and exciting class of compounds that have great promise and potential to treat both diabetes and obesity.
Mark Senner President and Director
Neither the TSX Venture Exchange nor its Regulation Services Provider (as that term is defined in the policies of the TSX Venture Exchange) accepts responsibility for the adequacy or accuracy of this release.
950-789 west pender street
vancouver, b.c., v6c 1h2
Direct: 604-641-4466
Fax: 604-608-5471
info@sironabiochem.com
Source: Marketwire
Agilux Laboratories Hires New Associate Director to Lead In Vitro ADMET Services Division
Last Updated on Thursday, 8 October 2009 12:22 Written by Editor Thursday, 8 October 2009 12:22
- Adrian Sheldon, Ph.D., Positions Contract Research Organization for Growth - WORCESTER, Mass.--(Business Wire)-- Agilux Laboratories, Inc., a Contract Research Organization (CRO) that provides bioanalytical and in vitro Absorption Distribution Metabolism Excretion Toxicology (ADMET) services for the biotechnology and pharmaceutical industries, has appointed Dr. Adrian Sheldon as associate director of In Vitro ADMET Services. In this role, Dr. Sheldon will build the In Vitro ADMET Services division offering testing services that allow biotechnology and pharmaceutical companies to screen drug candidates for desirable ADMET properties. Dr. Sheldon will leverage more than 17 years of industry experience, including establishing new business units for In Vitro ADMET and Immunochemistry within an established CRO. He will extend Agilux`s emphasis on customer service, rapid turnaround and exceptional data quality to the company`s newly formed In Vitro ADMET Services Testing Division. "We are excited to have someone with Adrian`s expertise, successful track record and demonstrated abilities at Agilux," said Jim Jersey, president and CEO at Agilux. "Adrian brings the right balance of scientific expertise and customer focus, which is consistent with Agilux`s mission of delivering high quality data at unprecedented speeds. We are confident that both the Agilux team and our clients will benefit from his unique skill set." Prior to Agilux, Dr. Sheldon served as associate director of In Vitro ADMET at Charles River Laboratories. Prior to Charles River Laboratories, Dr. Sheldon was group leader in Assay Development/HTS/In Vitro ADMET at ArQule where he co-managed a team responsible for screening compounds generated by the industry-leading combinatorial chemistry laboratory. He received his Ph.D. from Boston University and his A.B. from Harvard University. Dr. Sheldon has authored numerous scientific publications and holds two patents. "I am very pleased about joining the team at Agilux," stated Dr. Sheldon. "We have an incredible opportunity to change the way early stage development services are delivered and I am confident that I will be able to contribute to Agilux`s continuing success." About Agilux Laboratories, Inc. Agilux Laboratories, Inc. is a privately held contract research organization (CRO) focused on bioanlaytical and PK/PD testing services for the biotech and pharmaceutical industries. Leveraging industry and contract research experience of its management team, the company delivers high quality bioanlaytical chemistry and PK/PD data more rapidly. Agilux helps clients make better decisions during drug discovery and development by providing quality data earlier in the research process by using technologies and systems that increase turnaround speed well beyond industry standards. Founded in 2007 by industry experts Jim Jersey, Steve Guyan and Peter Glick, Agilux is headquartered in Worcester, MA and is funded by private equity firm, Ampersand Ventures. For more information, call 508-753-5000 or email sguyan@agiliuxlabs.com. Online at www.agiluxlabs.com. Agilux Laboratories, Inc. Steve Guyan Vice President, Sales and Marketing 508-762-4402 sguyan@agiluxlabs.com
Source: Reuters