Bio Screening Industry News

One element links the disparate areas of research: amyloids, which are fibrous, sticky protein aggregates. Some infectious bacteria use amyloids to attach to host cells and to build biofilms, which are bacterial communities bound together in a film that helps resist antibiotics and immune attacks.

Amyloids also form in the nervous system in Alzheimer’s disease, Parkinson’s disease and many other neurodegenerative disorders.

To probe amyloids’ contributions to neurodegenerative diseases, scientists altered potential UTI-fighting compounds originally selected for their ability to block bacteria’s ability to make amyloids and form biofilms. But when they brought the compounds back to UTI research after the neurology studies, they found the changes had also unexpectedly made them more effective UTI treatments.

“Thanks to this research, we have evidence for the first time that we may be able to use a single compound to impair both the bacteria’s ability to start infections and their ability to defend themselves in biofilms,” said senior author Scott J. Hultgren, Ph.D., the Helen L. Stoever Professor of Molecular Microbiology at Washington University.

The findings were reported online in Nature Chemical Biology.

The National Institutes of Health has estimated that over 80 percent of microbial infections are caused by bacteria growing in a biofilm, according to Hultgren. Scientists in Hultgren’s laboratory have worked for decades to understand the links between biofilms and UTIs.

“UTIs occur mainly in women and cause around $1.6 billion in medical expenses every year in the United States,” said co-lead author Jerome S. Pinkner, laboratory manager for Hultgren.

“We think it’s likely that women who are troubled by recurrent bouts of UTIs are actually being plagued by a single persistent infection that hides in biofilms to elude treatment,” Pinkner added.

Co-lead author Matthew R. Chapman, Ph.D., now associate professor of molecular, cellular and developmental biology at the University of Michigan, was a postdoctoral fellow in Hultgren’s lab in 2002 when he discovered that the same bacterium that causes most UTIs, Escherichia coli, deliberately makes amyloids. The amyloids go into fibers known as curli that are extruded by the bacteria to strengthen the structures of biofilms.

To treat UTIs, Hultgren’s lab has been working with Fredrik Almqvist, Ph.D., a chemist at the University of Umea in Sweden, to develop compounds that block bacteria’s ability to make curli, disrupting their ability to make biofilms and leaving them more vulnerable to antibiotics or immune system attacks.

Almqvist recently suggested altering a group of the most promising curli-blockers to see if they could also block the processes that form amyloids in Alzheimer’s disease.

The alterations worked: In laboratory tests, the new compounds prevented the protein fragment known as amyloid beta from aggregating into amyloid plaques like those found in the brain in Alzheimer’s disease.

When scientists took the new compounds back to a mouse model of UTIs, though, they received a surprise. The altered compounds were better at reducing the virulence of infections, inhibiting not only curli formation but also the formation of a second type of bacterial fibers, the pili.

“Pili aren’t made of amyloids, but they are essential to both biofilms and to the bacteria’s ability to initiate an infection,” Hultgren said.

Hultgren and colleagues are already developing even more potent infection and amyloid fighters, screening a library of thousands of chemicals similar to the most promising compounds from the study.

Chapman cautions that it’s too early to tell which, if any, of the compounds will be helpful in treating neurodegenerative diseases.

“Much neurodegenerative drug development has focused on ways to break up amyloids or prevent them from forming, but because amyloids may also be an important part of normal cellular physiology, we need to identify molecules that will target only the toxic amyloid state,” he said.

Source: farsnews.com

The Drugs for Neglected Diseases initiative (DNDi) has announced an agreement with drug giant Pfizer that will allow it access to the Pfizer library of novel chemical entities, in order to screen it for compounds that could be developed into new treatments for three of the most neglected infectious diseases of poverty: human African trypanosomiasis (HAT), visceral leishmaniasis (VL) and Chagas disease.

Pfizer vice president Dr Manos Perros said, “We are expanding our commitment to the fight against tropical diseases by joining forces with DNDi by sharing our collection of chemical compounds and the knowledge and expertise associated with these chemical entities”. His colleague Dr Sam Azoulay said, “We are confident that the significant resources and expertise that public-private partnerships such as this one bring together, will accelerate and significantly increase the chances of success in the search for effective new drugs against serious infections that disproportionately affect the poor”.

Under the agreement, scientists in institutes affiliated with DNDi will test at least 150,000 compounds in the Pfizer library against Trypanosoma brucei, Leishmania donovani and Trypanosoma cruzi, the kinetoplastid parasites that cause HAT, VL and Chagas disease, respectively. The researchers will seek compounds that show initial activity against the parasites, and thus might form the basis for novel drug discovery programmes to treat the diseases. The screening will be undertaken at the Eskitis Institute for Cell and Molecular Therapies, Griffith University in Brisbane, Australia (for HAT) and the Institut Pasteur Korea (VL and Chagas disease).

“This agreement provides us access to a compound library of novel chemical entities that has never been explored for kinetoplastid diseases. This marks an important step towards DNDi’s objective of building a robust portfolio and to feed the research and development pipeline with new promising compounds,” said Dr Shing Chang, R&D director at DNDi. In July this year, DNDi announced a similar agreement with Merck – see press release.

Within the same week as the finalising of its agreement with Pfizer, DNDi also announced it is to receive $15 million of Gates Foundation funding over the next five years, which it will use for the development of fexinidazole, currently the only new drug candidate in clinical development for sleeping sickness – see press release. Further information about DNDi is available here.

Source: tropika.net

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 Mice”. 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.”

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

Berlin-based Caprotec bioanalytics opened a U.S. subsidiary in Burlington, MA. The U.S. business will be responsible for North American sales, marketing, and support for the company’s Capture Compound Mass Spectrometry (CCMS) technology and related products.

Christian Jurinke, Ph.D., Caprotec’s head of product commercialization and distribution, has been appointed president of the new U.S. subsidiary. The business is also partnering with Genovative Solutions to help boost sales of CCMS products and services in North America.

The CCMS technology has been developed to target, capture, and isolate selected proteins, including membrane proteins, out of any complex biological sample, based on their functionality.

The approach uses synthetic Capture Compound molecules to interrogate native proteins, including lipophilic membrane proteins, in virtually any biological sample. Caprotec is commercializing CCMS through preconfigured caproKits™, and through contract services based on already available Capture Compounds. The company also works in collaboration with companies and researchers in areas including drug interaction protein profiling, drug target identification, and evaluating drug mode of action and off-target side effects.

The first two caproKits, SAH caproKit, and cAMP caproKit, were launched in January. CaproKits are currently available for protein kinases, cAMP- and cGMP-binding proteins, methyl transferases, and metalloproteases. New kits are also constantly being developed.

The CCMS process can be described as a homogeneous reverse high-throughput screening, Caprotec explains. In essence, the proteome is treated as a library and screened for individual proteins that interact with the highly selective Capture Compounds. The features of CCMS hinge on the multifunctionality of these synthetic Capture Compound molecules. Not only do Capture Compounds function selectively, e.g., for an enzyme substrate/inhibitor, a co-factor or drug candidate), but they also have a reactivity function, to covalently bind the protein target. A sorting function then pulls the Capture Compound-protein-complex directly out of cell lysates.

Source: genengnews.com

The last decade has seen a major expansion in the cancer drug pipeline and studies are continually underway to advance the arsenal of drugs and create more effective treatments and targeted therapies for patients.

To highlight results of more recent research, the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics International Conference will host a press briefing on “Drugs in the Pipeline.” Sara A. Courtneidge, Ph.D., D.Sc., professor and director of the Tumor Microenvironment Program, and director of academic affairs at the Burnham Institute for Medical Research, will moderate this press briefing.

“Conferences such as the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics International Conference play a very important role in advancing translational cancer research. Here, one can learn about the newest breakthroughs across the continuum of cancer research,” said Courtneidge.

Breakthroughs to date have been made in the development of anti-angiogenesis inhibitors that target the tumor vasculature and of modulators of gene expression and protein stability, according to Courtneidge. Many more agents have been added to the pipeline of cancer drugs, including inhibitors that target the BCR-ABL fusion protein and other kinases. Cytotoxic agents remain a mainstay of cancer therapy, and inhibitors of DNA repair and cancer stem cells show great promise.

The press briefing will take place on Monday, Nov. 16, 2009, from 1:00 p.m. to 2:00 p.m. ET, in Room 202 of the Hynes Convention Center in Boston, Mass.

Reporters who cannot attend in person may call using the following information:

U.S./Canada: (888) 282-7404
International: (706) 679-5207
Access Code: 36170264
Topic: AACR

Leading researchers will present new and exciting data on the role of hsp70 as a novel therapy for breast cancer; various drug compounds that kill leukemia stem cells and yet spare normal stem cells; tolerability results of cediranib for use in children with recurrent or refractory solid tumors; and sensitivity study results of olaparib for colorectal cancer cells containing a specific DNA repair defect.

“This research spans studies on the genetic makeup of cancer cells, validation studies on the roles of key signaling proteins and pathways, the development of novel agents, and the testing of those agents in a variety of pre-clinical and clinical settings,” Courtneidge added.

The following abstracts will be presented during this press briefing:

# B21. Targeting autophagy induced by pan-HDAC inhibitor panobinostat and promoted by acetylated hsp70: A novel therapy for breast cancer

Targeting heat shock response protein with panobinostat, combined with an autophagy inhibitor, is an effective treatment strategy against growing stress cells in breast cancer.

“Clearly this points to a very new approach of targeting heat shock response in combination treatment,” said Kapil Bhalla, M.D., director of the Medical College of Georgia Cancer Center, professor of medicine in the Department of Medicine, Division of Hematology-Oncology at the Medical College of Georgia, and vice president for cancer research at the Medical College of Georgia.

Panobinostat is a potent histone deacetylase (HDAC) inhibitor that has been shown to induce cell death of tumor cell lines, but not the normal cells. In breast cancer cells where programmed cell death is inhibited, pan-HDAC inhibitor treatment induces autophagy, which allows the breast cancer cells to escape elimination.

Bhalla and colleagues evaluated the stress phenotype of breast cancer cells in the mammary fat pad of mice when mediated by two heat shock proteins — hsp90 and hsp70, which help to promote cancer survival. The researchers wanted to determine how these inhibitors that deacetylate proteins and histones affect the cell’s function.

“Basically we forced the cancer cell to have autophagy and then pulled the rug from under it by having an autophagy inhibitor take that away,” said Bhalla.

Treatment with panobinostat induced acetylation of amino acid lysine in the hsp70 protein. With growing tumor size they found an increase in hsp70, heat shock response and autophagy.

“Panobinostat accentuates stress, causes autophagy, and sets up the cell to be eliminated by autophagy inhibitors,” Bhalla said.

Panobinostat is not FDA approved for use in breast cancer.
# A51. Identification of compounds targeting human leukemia stem cells

Researchers at the University of Michigan, Ann Arbor, and the University Health Network, Toronto, have found a new paradigm for screening against leukemia stem cells that can target them and spare blood-forming stem cells at the same time.

The researchers identified small molecules, potentially novel or those currently known, that kill leukemia stem cells, but not normal blood-forming hematopoietic stem cells, which are multipotent stem cells that give rise to all blood types. Three of the 10 compounds they studied targeted leukemia stem cells: ciclopirox olamine, etoposide and kinetin riboside.

“Treatment with these compounds, at the appropriate doses, would kill the leukemia cells and potentially minimize blood system side effects, such as anemia,” said Sean McDermott, Ph.D., research investigator in the Department of Internal Medicine, Hematology-Oncology at the University of Michigan Medical School.

In total, the researchers screened a collection of 4,000 small molecules using two novel leukemia cell lines that have properties of leukemia stem cells. Compounds that killed these leukemia cells were further tested on normal hematopoietic stem cells to remove toxic compounds.

“Overall, to find three compounds that target the leukemia stem cell, all with vastly different mechanisms, is extremely surprising and bodes well for future drug discovery efforts,” said McDermott.

Cells from 51 patients with acute myeloid leukemia (AML) and 12 patients with chronic myelogenuous leukemia (CML) were screened with one of the drugs, etoposide. The researchers were surprised by the etoposide results, which showed that the drug may target the leukemia stem cell in 30 percent of patients with AML and 67 percent of those with CML. These patients might benefit from treatment with this chemotherapeutic drug.

“Screening of larger libraries hopefully will identify even more agents for the cancer pipeline,” he added.

Follow-up studies are currently planned for ciclopirox olamine and it would be beneficial in evaluating low-dose etoposide as a single agent. Kinetin riboside may be tested in a clinical setting in the future, according to McDermott.

# A5. Phase I trial and pharmacokinetic study of cediranib in children with recurrent or refractory solid tumors

Results of a new study show that cediranib can be administered safely to children and adolescents with cancer, and that the side effects are tolerable. Preliminary evidence further showed that the drug may have activity in childhood sarcomas.

“There are a number of antiangiogenic agents, like cediranib, in development for adult cancers,” said researcher Elizabeth Fox, M.D., M.S.C.R., staff clinician in the Pediatric Oncology Branch at the National Cancer Institute. “Encouraging results seen in this trial provide a rationale for future clinical trials of cediranib and other antiangiogenic agents in childhood cancer.”

Cediranib is an oral drug that inhibits vascular endothelial growth factor receptor. The recommended dose in adults is 20 mg to 30 mg administered daily every day for 28 days.

Fox and colleagues tested the toxicity and tolerance of this drug when given in 28-day cycles to patients 2 to 19 years old with malignant solid tumors to determine the appropriate dose of cediranib for this age group. Patients who participated in this phase I study had not responded to or recurred after conventional therapy.

Among the 13 patients enrolled, once daily dosing of 12 mg/m2 of cediranib was tolerable. Thus far, three patients have experienced partial shrinkage of their tumor while receiving the antiangiogenic agent. Side effects in children were similar to those seen in adults on cediranib: dose-limiting toxicities were diarrhea, nausea, vomiting, lethargy and high blood pressure.

“This outcome is encouraging and provides evidence that cediranib should be further studied in future clinical trials in young patients with these and other sarcomas to determine the activity of this new agent,” Fox said. “Hopefully, newer classes of anti-cancer drugs currently being developed will have fewer acute and long-term side effects than the chemotherapy that we currently use to treat childhood cancers.”

The researchers are currently evaluating the effects with 17 mg/m2 of cediranib and proposed to the Children’s Oncology Group that a phase II study be conducted in selected childhood solid tumors.

# A114. Preclinical evaluation of the PARP inhibitor olaparib in homologous recombination deficient (HRD) MRE11 mutant microsatellite instable (MSI) colorectal cancer

The investigational cancer therapy olaparib demonstrated activity against colorectal cancer cells, which suggests that microsatellite instable colorectal cancer represents a potential patient population that could benefit from treatment with this agent.

Researchers have already evaluated the use of the oral poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor olaparib and its antitumor activity pre-clinically and in patients with breast and ovarian cancer that contain a specific DNA repair defect in the form of BRCA1 and BRCA2 mutations. These gene mutations are associated with hereditary breast and ovarian cancer and play a major role in the repair of DNA by the homologous recombination repair pathway. PARPs also play a major role in DNA repair, by working in an alternative pathway.

Olaparib exploits the “Achilles’ heel” of homologous recombination deficient cancers by blocking another DNA repair pathway in these already compromised cancer cells, therefore leading to an overload of DNA damage and resulting in tumor cell death. The activity of one such homologous recombination gene, MRE11, is lost as a consequence of microsatellite instability in colorectal cancer cells.

“DNA damage is occurring all the time in our cells and a number of mechanisms have evolved to repair this damage that include the PARP and the homologous recombination repair pathways,” said Mark O’Connor, Ph.D., chief scientist at KuDOS Pharmaceuticals Ltd., United Kingdom.

The aim of this study was to determine if microsatellite instability and MRE11 status correlated with sensitivity to olaparib. Olaparib is an oral anti-cancer drug in early development for the treatment of certain types of breast and ovarian cancer.

The researchers found the majority of colorectal cancer cell lines sensitive to olaparib correlated with microsatellite instability status and had MRE11 mutations. Furthermore, all olaparib-sensitive colorectal cancer cell lines were homologous recombination deficient.

“These results reinforce the idea that PARP inhibition might have broader clinical utility than in BRCA-deficient tumors alone,” said O’Connor. “They support the idea of using targeted cancer therapies in defined molecular genetic backgrounds that exploit specific DNA repair deficiencies in the cancer to be treated.”

http://www.eortc.be/

Source: news-medical.net

Scientists at Washington University School of Medicine in St. Louis are investigating a new way to fight the flu.

Source: mednews.wustl.edu

European chemists have discovered that both mirror-image forms of a particular compound can bind at the same time in the same site of an enzyme, a phenomenon that has never been seen before. The finding has significance for drug discovery screening and studies of how small molecules interact with proteins.

Rolf Breinbauer from Graz University of Technology, Austria, and Wulf Blankenfeldt from the Max Planck Institute of Molecular Physiology in Dortmund, Germany, were studying a metabolic enzyme from a species of the bacterium Burkholderia cepacia, using racemic mixtures of chiral probe molecules to find ones that bound in the enzyme’s active site. In most cases only one form of a chiral (or ‘handed’) molecule would bind at once, but they found that in one instance both enantiomeric forms occupied the binding site at the same time.

‘If you read the textbooks about enantiomers,’ says Breinbauer, ‘there’s a simplified notion that one enantiomer is good and the other is either bad or just idle.’ He explains that for most proteins (apart from certain enzymes that have evolved to cope with wide ranges of substrate molecules) either only one enantiomer will bind, or both can bind individually - with the assumption that one form will be significantly more active than the other. ‘Our findings show that the world is more complicated,’ he adds.

While each individual enantiomer can bind to the enzyme seperately, Breinbauer notes that the arrangement of the molecules within the binding site is quite different when both bind together. This could lead to cooperative effects, producing either an enhanced or diminished response relative to the individual enantiomers.

He adds that this could have relevance in drug discovery screening, where mixtures of both enantiomers of chiral compounds are routinely screened together to find initial hits. ‘People need to consider more options when interpreting binding data from racemic mixtures.’

Dafydd Owen of Pfizer Research Chemistry in  Sandwich, UK, agrees that the finding is an important reminder that chemists need to be open-minded about interpreting screening data. It also highlights the inherent trade-offs made when screening mixtures - particularly in high-throughput screens when mixtures of several compounds are tested at once.

Owen sees most interest in the discovery in the area of fragment-based drug discovery, where small ‘fragment’ molecules found to bind to a drug target are linked together to make potential drug molecules. ‘As a medicinal chemist,’ he adds, ‘my immediate thought was to join the two structures together to incorporate the best of each and make a hybrid.’ He points out, however, that from a fragment point of view it is almost irrelevant to the enzyme that the two molecules happen to be mirror images of each other, ‘despite their apparent similarity, nature views enantiomers as very different molecules’.

Phillip Broadwith

Source: rsc.org

Scientists at the University of North Carolina at Chapel Hill School of Medicine and the University of California, San Francisco have developed and experimentally tested a technique to predict new target diseases for existing drugs.

The researchers developed a computational method that compares how similar the structures of all known drugs are to the naturally occurring binding partners — known as ligands — of disease targets within the cell. In a study published this week in Nature, the scientists showed that the method predicts potential new uses as well as unexpected side effects of approved drugs.”This approach uncovered interactions between drugs and targets that we never could have predicted simply by looking at the chemical structures,” said senior study author Bryan Roth, M.D., Ph.D., professor of pharmacology and director of the National Institute of Mental Health Psychoactive Drug Screening Program at UNC. “We may now have a way to predict what side effects are likely to occur from treatment before we even put a drug into clinical testing.” Roth is also a member of the UNC Lineberger Comprehensive Cancer Center.

Many of the most successful drugs on the market today are being prescribed for ailments that are quite different from the ones they were originally designed to treat. Viagra, for instance, was once intended for coronary heart disease but now is used to combat erectile dysfunction. The discovery of surprising uses of developed drugs can sometimes be the result of serendipity, as unforeseen side effects emerge from clinical trials. In the past, researchers have tried to predict drug interactions by looking for chemical similarities among the possible targets of pharmaceutical compounds.

However, some drug targets which look very similar to one another bind very different ligands, and some targets that don’t have any obvious similarity bind similar ligands, says Brian Shoichet, Ph.D., co-senior study author and professor of pharmaceutical chemistry at the University of California at San Francisco. “So if instead we were to organize targets by the ligands they recognize, it could reveal different patterns than traditional approaches, and illuminate new opportunities for drugs to bind to unexpected targets.”

A team of researchers led by Roth and Shoichet did just that, comparing the structures of 3,365 FDA-approved and investigational drugs against the structures of hundreds of targets, defining each target by its ligands. They then honed in on thirty of the strongest predictions, validating the actual physical interactions between the drugs and targets in wet laboratory experiments.

In one of their follow-up experiments, the scientists investigated the molecular targets of the hallucinogenic substance dimethyltrytamine (DMT), which had previously been postulated to act through a site known as the sigma-1 receptor. Using the computational approach, Roth and colleagues found that DMT had a high affinity for serotonin receptors, including the binding site for LSD, another hallucinogen.

They also showed that the substance is hallucinogenic in normal mouse models but not in ones lacking the serotonin receptor. Roth says the power of their approach is it can be used to uncover the real targets of pharmaceutical compounds quickly and efficiently, and will probably lead to a greater understanding of the many molecular targets of each drug.

“Drugs are not as selective as we once thought,” said Roth, who is also a professor in the School of Pharmacy’s medicinal chemistry and natural products division. “It turns out that the most non-selective drugs are frequently the most effective for complex diseases. Rather than ‘magic bullets,’ we need to come up with ‘magic shotguns’ that hit more than one molecular target at a time. We could use this computational approach to identify the drugs that hit the right targets and miss the wrong ones.”

Study co-authors from UNC include Vincent Setola, research associate professor; Atheir Abbas, former graduate student; Sandra J. Hufeisen, senior research assistant; Niels H. Jensen, research associate; Michael B. Kuijer, research technician; Roberto C. Matos, research technician; Thuy B. Tran, research technician; Ryan Whaley, research technician; and Richard A. Glennon. The paper’s first author is Dr. Michael Keiser, from the UCSF side of the collaboration. Also from UCSF were Drs. John Irwin, Christian Laggner and Jerome Hert, and PharmDs Kelan Thomas and Douglas Edwards.

Funding for the studies at UNC and at UCSF came from the National Institutes of Health.

ScienceDaily (Nov. 7, 2009)

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,”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.”

Chen says he is proud of the work, which is “truly translational science.”

“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.”

Provided by Duke University Medical Center

physorg.com