Cold Spring Harbor: A Grab Bag from the Drug Discovery Folks
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Drug discovery for neurodegenerative diseases continues on all fronts, from studies of fundamental biology to the development of new therapeutic compounds. The Cold Spring Harbor conference, Neurodegenerative Diseases: Biology and Therapeutics, held 30 November through 3 December, 2006, offered something for everyone involved in this process. A few highlights from the meeting are presented below.
The National Institute of Health (NIH), foundations, academia, and pharmaceutical companies have all entered the fray by developing tools and new strategies to facilitate drug discovery. Christopher Austin from the NIH opened the meeting with a presentation about the Molecular Libraries Screening Center Network (MLSCN), a major component of the Molecular Libraries and Imaging Initiative of the NIH Roadmap for Medical Research. Ten NIH-funded screening centers around the country make up the MLSCN. They perform high-throughput screening (HTS) and develop chemical probes for investigators in academia who have identified novel therapeutic targets but lack the tools needed to identify hits and develop them further. Each of the screening centers offers different technologies. Investigators submit their assay to the MLSCN, which organizes a peer review to determine whether the assay is ready for HTS and which center would provide the best match. The centers have access to the 100,000-compound Small Molecular Repository, a collection of compounds the NIH has assembled for HTS through a contract with the company BioFocus DPI in South San Francisco, California. Scientists at the MLSCN center optimize the assay and then screen the compound collection to find a candidate probe. Analogs synthesized during the optimization may be added to the compound repository; then the MLSCN center returns data to the investigator. MLSCN also deposits the data in a publicly accessible database called PubChem, which is linked to other NIH databases. Austin said that although data are freely shared on PubChem, investigators are unlikely to get scooped. Not only do they usually have the data first, but they also are likely to be ahead on synthesis of the compounds. PubChem provides a rich source of pharmacologic data that can be applied to other research questions.
The resources available to pharmaceutical companies are even more elaborate, according to John Houston of Bristol-Myers Squibb Pharmaceutical Research Institute in Wallingford, Connecticut. Houston described an HTS program that can produce 500,000 to one million data points in 2 to 3 weeks, using many different assay technologies and screening systems. This integrated program allows a candidate compound to flow seamlessly through the drug discovery process, from selection of the initial chemical entity to evaluation of lead compounds, and it yields a compound profile with highly annotated data. The neuroscience group at Bristol-Myers Squibb focuses on schizophrenia, anxiety/depression, and Alzheimer’s (AD), Houston said, but compound information gathered during this process is available to scientists working in other therapeutic areas within the company, as well.
Foundations that focus on a particular disease are also developing new strategies for drug discovery. Doug MacDonald works at CHDI, Inc. in Los Angeles, California, a non-profit biotech organization dedicated solely to finding treatments for Huntington disease (HD.) He described a three-pronged approach to drug discovery. It includes internally driven programs, external collaborations with other biotech organizations, and compound development agreements with pharmaceutical companies who have an advanced compound that looks promising for HD. For the internal “prong,” CHDI functions as a virtual drug discovery engine. It uses contract research organizations (CROs), for assay development, screening, medicinal chemistry, structural biology, analytical chemistry, bioinformatics, pharmacokinetics, formulations, and toxicology to accomplish the tasks that CHDI has identified as essential for a given project. For example, one project in the CHDI portfolio focuses on transglutaminase 2; this protein that been validated as a possible HD therapeutic target in several reports, but there are currently no good validating ligands for it. CHDI established collaborations with scientists and CROs to identify potent and selective inhibitors that would cross the blood brain barrier. Working with the biotechnology company Evotec AG in Hamburg, Germany, they screened nearly 300,000 compounds and are now pursuing 21 chemical “clusters” that were identified based on structure-activity relationships. Next, they plan to conduct cell-based assays and then tests in HD mouse models.
Secondly, CHDI has established collaborations with biotechnology companies to apply specific technologies and expertise to HD drug discovery. As an example, MacDonald described one such collaboration with CombinatoRx, Inc. in Cambridge, Massachusetts, where combinations of existing drugs are screened in high throughput HD assays to find compounds that act synergistically against HD targets. And thirdly, CHDI has contracted with PsychoGenics, Inc. in Tarrytown, New York, to test candidate drugs from large pharmaceutical and other biotech companies companies in proof-of-mechanism studies using HD mouse models.
Meanwhile, academic institutions and medical centers are making their own inroads into drug discovery. Linda Van Eldik is at the Center of Drug Discovery and Chemical Biology at Northwestern University in Chicago, Illinois. Van Eldik talked about a “crisis in drug discovery,” where the number of new chemical entities is flat or declining despite increased research funding. She called the situation especially grave for neurologic diseases. She and other speakers agreed that planning of the early stages of drug discovery must improve to decrease risk, lower cost, save time, and reduce late-stage failures.
Van Eldik described a de novo lead discovery approach to find compounds that target glia as mediators of neuroinflammation in AD (Wing et al., 2006). Her team started with a particular chemical skeleton called an inactive aminopyridazine fragment. That’s because compounds built on this structure have proven safe and effective as CNS drugs. The scientists then diversified the fragment chemically, designing compounds with properties such as low molecular weight, moderate lipophilicity, as well as good solubility, safety, and bioavailability. Next, they used cell-based primary screens to identify compounds that inhibit glial activation, followed by secondary screens of compounds in animal models. In less than 2 years, the scientists identified a lead compound, refined it with medicinal chemistry to identify a candidate for clinical development, and worked out a chemical process to produce it (Hu et al., 2006). In mouse AD models, the compound, Minozac, suppressed upregulation of proinflammatory cytokines, decreased astrocyte and microglial activation, prevented loss of synaptic proteins, and attenuated behavioral deficits. It is currently in clinical development for AD and related disorders at a biotechnology company that has licensed Minozac and similar compounds, VanEldik said.
Minozac is one of a dozen compounds discussed at the meeting as potential therapies for AD or other neurodegenerative diseases. Many of the other AD treatments are focusing on amyloid. Paul Aisen of Georgetown University identified three categories of anti-amyloid therapies: those that affect secretase cleavage, those that target the amyloid peptide itself, and those that have anti-inflammatory, antioxidant, or neuroprotective properties. Among those that act on the secretase cleavage site or directly on the amyloid peptide, there are both immunological and non-immunological approaches.
Ron Black of Wyeth Research, in Collegeville, Pennsylvania, reported results from a phase 1 trial of 30 patients with mild to moderate AD who received a single dose of bapineuzumab, a humanized monoclonal antibody to Aβ. These data were originally presented at the Geneva-Springfield Symposium in April, 2006. Bapineuzumab is a second-generation immunotherapeutic from Wyeth and Elan Pharmaceuticals in South San Francisco, California. At the highest dose of 5 mg/kg, three of 10 patients developed MRI abnormalities, which were not seen among the 12 patients who got lower doses. Four months after the injection, cognitive performance as assessed with the Mini-Mental State Exam (MMSE) improved with lower doses, reaching statistical significance at 1.5 mg/kg. Treatment also caused a transient increase in plasma Aβ. A phase 2 trial started in 2005, but Black did not present data on it.
Beka Solomon from Tel-Aviv University in Tel-Aviv, Israel, developed a different immunological approach using antibodies against the β-secretase cleavage site on the amyloid precursor protein (APP, Arbel et al., 2005). In transgenic mice, both the Tg2576 line and another also expressing the APP Swedish mutation, animals treated with the antibody performed better on an object recognition test in a dose-dependent manner, and also showed less microglial activation in the hippocampus, dentate gyrus, and parietal cortex. Treatment with this antibody led to fewer brain microhemorrhages than were seen in mice treated with some other anti-Aβ therapies that involve a redistribution of amyloid from the parenchyma to blood vessels (Morgan, 2005). Solomon said that her proposed immunotherapy does not involve such a redistribution, and thus is less likely to cause microbleeds.
Among non-immunologic anti-Aβ therapies, Paul Aisen of Georgetown University in Washington, D.C., and Lara Fallon of Neurochem in Laval, Quebec, Canada, discussed tramiprosate (AlzhemedTM). This small molecule therapeutic is believed to prevent amyloid deposition by binding to soluble Aβ. Phase 1 and 2 clinical studies suggested that tramiprosate safely reduces CSF Aβ42 levels in mild to moderate AD patients, and in an open-label, uncontrolled extension of the phase 2 trial, people with mild AD so far have shown no significant cognitive decline at 20 months, said Aisen. Results for the North American phase 3 trial are expected in spring 2007.
On the basic science front, Scott Small of Columbia University in New York City studies the basic cell biology of AD to understand key mechanistic pathways that may be vulnerable to disease pathogenesis. Small initially demonstrated with brain imaging and gene expression profiling that late-onset AD patients have defects in the retromer trafficking complex, which is important for protein sorting (Small et al., 2005). Then Small went on to show in cell culture and in a knockout mouse model that such defects lead to accelerated Aβ production, thus implicating retromer dysfunction as a therapeutic target. More recently, Small and colleagues have found a polymorphism in a retromer-related molecule that significantly increases the risk for AD (in press).”—Lisa J. Bain.
Lisa J. Bain is a freelance science writer in Philadelphia.
References
Therapeutics Citations
Paper Citations
- Wing LK, Behanna HA, Van Eldik LJ, Watterson DM, Ralay Ranaivo H. De novo and molecular target-independent discovery of orally bioavailable lead compounds for neurological disorders. Curr Alzheimer Res. 2006 Jul;3(3):205-14. PubMed.
- Hu W, Ralay Ranaivo H, Roy SM, Behanna HA, Wing LK, Munoz L, Guo L, Van Eldik LJ, Watterson DM. Development of a novel therapeutic suppressor of brain proinflammatory cytokine up-regulation that attenuates synaptic dysfunction and behavioral deficits. Bioorg Med Chem Lett. 2007 Jan 15;17(2):414-8. PubMed.
- Arbel M, Yacoby I, Solomon B. Inhibition of amyloid precursor protein processing by beta-secretase through site-directed antibodies. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7718-23. PubMed.
- Small SA, Kent K, Pierce A, Leung C, Kang MS, Okada H, Honig L, Vonsattel JP, Kim TW. Model-guided microarray implicates the retromer complex in Alzheimer's disease. Ann Neurol. 2005 Dec;58(6):909-19. PubMed.
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It's interesting that Scott Small has found that defects in the retromer trafficking complex lead to accelerated Aβ production. The retromer complex is involved in the retrograde transport of the CI-M6PR (cation-independent mannose 6-phosphate receptor) from endosomes to the Golgi (1). Guiseppina Tesco and Rudy Tanzi (2) have found reduced levels of GGA3 in AD brain, and this is also involved in protein trafficking (2). Previously referenced studies report that RNA interference (RNAi) of GGA3 expression results in accumulation of the cation-independent mannose-6 phosphate receptor and internalized epidermal growth factor (EGF) within enlarged early endosomes, and PS-FAD expressed higher levels of the cation-independent mannose-6 phosphate receptor (3).
See also:
Comment by Giuseppina Tesco
Comment by Mary Reid
References:
Damen E, Krieger E, Nielsen JE, Eygensteyn J, van Leeuwen JE. The human Vps29 retromer component is a metallo-phosphoesterase for a cation-independent mannose 6-phosphate receptor substrate peptide. Biochem J. 2006 Sep 15;398(3):399-409. PubMed.
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