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Tuesday, April 25
12:00pm Conference Registration
FRONTIERS AND NEW APPROACHES TO
MARINE DRUG DISCOVERY
1:30 Chairperson’s Remarks
*William Fenical, Ph.D., Professor of Oceanography, Director Center for Marine Biotechnology and Biomedicine Scripps
1:45 The Deep Oceans, a Unexplored and Robust Resource for Drug Discovery
*William Fenical, Ph.D., Professor of Oceanography, Director Center for Marine Biotechnology and Biomedicine Scripps Institution of Oceanography, University of California, San Diego
For more than 50 years, soil-derived actinomycetes provided a major pharmaceutical resource for the discovery of antibiotics and related bioactive compounds. During this period, a major effort was undertaken to examine virtually every terrestrial habitat. The oceans, representing >70% of the Earth’s surface, were never seriously considered as a source for actinomycete diversity. This is because the prevailing view was that actinomycetes were exclusively terrestrial, because the marine environment is far more difficult to sample and because little information was available to insure the successful cultivation of “marine bacteria.” During the last 3-4 years, we have examined tropical marine environments and undertaken a systematic approach to cultivate and identify “marine actinomycetes”, those uniquely adapted to growth in the sea. Our studies have revealed that taxonomically-unique representatives of the all the actinomycete families can readily be isolated in culture. Overall, our results suggest that actinomycetes are a significant component of the deep ocean sediment bacterial communities. At least 13 diverse groups, which appear to be entirely new genera, have been isolated. In culture, we are now observing the production of a diversity of bioactive secondary metabolites, which possess unprecedented carbon skeletons and functionalities. This talk will emphasize the discovery of an entirely new source for chemical diversity for drug discovery.
2:15 Synergizing Drug Discovery from Marine Cyanobacteria with Genetic Approaches to Natural Products Biosynthesis
Kerry McPhail, Ph.D., Assistant Professor, Senior Research, College of Pharmacy
Presenter, William Gerwick, Ph.D., Author
Marine cyanobacteria are incredibly rich sources of structurally-unique natural products which show powerful biological properties, especially to cancer and related diseases. Our drug discovery program at the CMBB focuses on mainly tropical marine algae and cyanobacteria, and uses a combination of sophisticated drug screening technologies in concert with modern methods of isolation and structure elucidation. In addition, for both basic scientific and practical reasons, we are fascinated to learn how these ancient marine organisms assemble these complex natural products, and we use a combination of classical and molecular genetic approaches in this pursuit. Ultimately, knowledge of this biochemical machinery will enable our production of these in scaled-up quantities through heterologous expression and fermentation, and to manipulate these pathways in innovative ways to create new molecules of diverse structure.
2:45 Mining Marine Actinomycete Genomes for Natural Products and Pathways
Bradley S. Moore, Ph.D., Professor of Oceanography and Pharmaceutical Sciences Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego
The world’s oceans are massively complex and consist of diverse assemblages of life forms that occur in environments of extreme variations in pressure, salinity, and temperature. Marine microorganisms have evolved unique metabolic and physiological capabilities to ensure their survival in these diverse habitats. The recent documentation that marine microorganisms produce chemically and biologically novel metabolites that are not observed from terrestrial microorganisms points to the ocean, and its microbiological resources, as an entirely new source for the discovery of new drug candidates. The discovery of diverse actinomycetes from the marine environment in particular has led to the description of new, chemically prolific
taxa. In some cases, the discovery of novel natural product chemistry is extraordinarily high. Together with this novel chemistry is the opportunity to discover and exploit new biosynthetic enzymes and metabolic pathways for the treatment of human health. This lecture will highlight several new marine actinomycete secondary metabolic pathways, including those involved in the biosynthesis of the potent 20S proteasome inhibitor salinosporamide A from the obligate marine actinomycete Salinispora
tropicalis, the novel meroterpenoids marinone and neomarinone from the MAR4
clade, and the polyketide antibiotic enterocin from a Hawaiian Streptomycete.
3:15 Networking Refreshment Break, Poster and Exhibit Viewing
4:00 Nanomole-Scale Natural Products
Tadeusz F. Molinski, Ph.D., Professor of Chemistry and Pharmaceutical Sciences Center for Marine Biotechnology and Biomedicine, Department of Chemistry and Biochemistry and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego
Marine natural products from non-culturable, exotic environmental samples (e.g. deep sea organisms,
biofilms) present new challenges for natural products discovery that necessitate methods for chemical structure determination that push the envelope of sensitivity. Mass spectrometry holds a premium in absolute sensitivity, but advances in NMR instrumentation (e.g.
microcapillary-probes) now allow us to contemplate ‘nanomole-scale’ natural products chemistry from sources of limited accessibility. In this talk I will highlight our recent results that push the envelope in terms of structural and stereochemical determination of natural products.
4:30 Solutions to the Supply Issue Hampering the Development of Marine Natural Products as Therapeutic Agents
Russell Kerr, Ph.D., Professor, Department of Chemistry & Biochemistry, Director of the Center of Excellence in Biomedical and Marine Biotechnology, Florida Atlantic University
Natural products have played a critical role in the discovery of biologically-active small molecules that have either become therapeutic agents themselves, or have provided the template for such therapeutic agents. The marine environment has proven to be an extremely rich source of novel natural products with a variety of biomedical applications. However, it is clear that the question of supply of these compounds presents a significant hurdle in the transformation of the marine natural product into a commercial entity. This presentation will discuss the pros and cons of potential approaches to marine natural product production with a focus on
Understanding the Mechanism of Inhibition of the 20S Proteasome by NPI-0052, a Novel Marine-Derived Proteasome Inhibitor
Barbara Potts, Ph.D., Vice President Chemistry, Nereus Pharmaceuticals
NPI-0052 is a highly potent, marine actinomycete-derived inhibitor of the 20S proteasome that is currently in development for the treatment of cancer. Structure-activity relationship studies have highlighted certain functional groups as being critical to the irreversible inhibition of the proteolytic cleavage of protein
substrates. These results have been confirmed through X-ray crystallographic analysis of NPI-0052 in complex with the yeast 20S proteasome. Together, the mechanism of inhibition of the 20S proteasome has been elucidated. Details of the structural features that are involved in proteasome binding and inhibition will be presented.
Walking Tour of the Scripps Institution of Oceanography and Reception at the
Birch Aquarium at Scripps 5:30 - 9:30
|All Drug Discovery Chemistry delegates are cordially invited to a special event at the Scripps Institution of Oceanography
(SIO) and Birch Aquarium at Scripps. Join William Fenical, Ph.D., Professor of Oceanography, Director Center for Marine Biotechnology and Biomedicine
(CMBB) at Scripps and his colleagues, William H. Gerwick, Ph.D., Bradley S. Moore, Ph.D., and Taduesz F.
Molinski, Ph.D., as we enter their research domain. During a walking tour of these breathtaking grounds, we will visit several the Scripps Institution highlights including their research laboratories. A reception will follow at the Birch Aquarium at
SIO. Located on a coastal bluff overlooking La Jolla Shores beach at Scripps, the Birch Aquarium is the public exploration center for the Scripps Institution of Oceanography at University of California, San Diego. The aquarium museum features a rotating gallery of exhibitions based upon cutting-edge research by SIO explorers. Buses will leave promptly following the end of today's programs.
Wednesday, April 26
NATURAL PRODUCT INSPIRED LEAD DISCOVERY:
Enhancing Chemical Diversity
8:00am Chairperson’s Remarks
Dr. Frank Koehn, Head Natural Product Chemistry Group, Natural Products Structural Chemistry, Wyeth
Genomics of Secondary Metabolite Biosynthesis as a Platform for Drug Discovery
James McAlpine, Ph.D., Vice President Chemistry & Discovery, Ecopia BioSciences Inc.
A database built on the last decade's discoveries of the genes which drive the biosynthesis of complex secondary metabolites, together with appropriate database mining tools provides a completely new approach to natural product discovery. A modest investment in information technology can unearth the key to the NCE potential of any organism and hence provide guidance to discovey, help in structure elucidation and a quantum jump in the efficiency of a project.
Plant Roots as Sources of Novel Small Molecule Natural Products
Barry Marrs, Ph.D., Corporate Technology Officer, Athena Biotechnologies, Inc.
The vast biodiversity of the plant kingdom remains largely untapped for drug discovery. Although plants have been recognized for generations as important sources of medicinal chemicals, they have not been properly exploited during past attempts to discover new compounds. Plant roots are very well developed chemical factories and can be stimulated to produce highly bioactive defense molecules, but without >proper stimulation, very little of their repertoire is present to be discovered. AthenaBio’s BioSource™ Library, produced and purified from plants grown hydroponically under controlled conditions and stimulated to produce defense molecules, contains novel small molecule natural products that are reproducible, scaleable and affordable.
9:10 Engineering Metabolic Pathways in Plants
Steven C. Bobzin, Ph.D., Director, Natural Products Chemistry, Ceres, Inc.
The genomics era has provided natural products chemists with a collection of tools to maximize the value of the chemical diversity found in plants. Genes comprising the biosynthetic pathways of plant natural products are being identified and deployed to increase the yield of economically valuable compounds and to identify new leads. These technologies will enable the development of difficult to produce plant natural products thereby addressing one of the common shortcomings of natural products discovery - the ability to scale-up production. These technologies also create novel discovery strategies to identify new leads from pharmacologically relevant structural scaffolds.
9:40 Networking Coffee Break, Poster and Exhibit Viewing
10:10 Bringing Back Nature to Drug Discovery
Natural Molecules in an Antibacterial Program
Mark O’Neil-Johnson, Ph.D., Senior Director, Scientific Development, Sequoia Sciences, Inc.
Molecules from nature have provided a vast majority of antibacterial compounds that are currently on the market today. Sequoia Sciences was built around advanced chemical technologies, creating a chemically diverse set of plant natural products in an HTS library format and applying this to an internal antibacterial program. Sequoia’s internal research program and collaborations with Washington University School of Medicine and Montana State University’s Center for Biofilm Engineering have discovered new inhibitors of bacterial
biofilms. Examples of a set of compounds that exhibit remarkable activity against uropathogenic clinical strains of E. coli will be detailed.
10:40 Natural Product Redux: Potent Antibacterial Agents from Hygromycin A
Steven J. Brickner, Ph.D., Research Fellow, Pfizer Inc.
An analysis of known antibacterial natural products in the literature as leads for a medicinal chemistry program led us to extensively re-examine Hygromycin A. The talk will describe key SAR studies that allowed us to identify potent truncated Hygromycin A compounds, several having oral efficacy commensurate with that of linezolid in murine models of multiresistant Gram-positive infections, but found to have a toleration issue in mouse safety studies. Further modification to address the toleration issue did identify a potent new series, with indications of a significantly improved toleration profile.
11:10 HTS and Pure Natural Products Libraries - Opposites Attract!
Hajo Schiewe, Ph.D., Director of Scientific Development, AnalytiCon Discovery GmbH
The innovation gap in the pharmaceutical industry as demonstrated by the increasing imbalance of R&D expenditures and numbers of NME per year is still growing. The resulting reconsideration of a re-entry into NP-based drug discovery is gaining momentum in the pharmaceutical industry, but has to take recent developments into account. A state-of-the-art re-introduction of NP to the drug discovery process needs to cope with increased speed due to automation and miniaturization; thus the time-consuming bioassay-guided extract screening is no longer appropriate. One very efficient way to make natural products available for screening is to generate libraries of pure; fully structure elucidated compounds, which makes NP HTS compatible. To achieve this, we designed the MEGAbolite process, which has yielded more than 22,000 pure NP with elucidated structure in the past five years. It will be shown that by introduction of a rigorous dereplication tool it possible to design such libraries by excluding unwanted compounds.
11:40 Technology Watch (Sponsorship Available)
12:00pm Lunch on Your Own (Sponsorship Available)
MEETING the CHALLENGES:
New Methodologies in Screening and Synthesis
1:45 Chairperson’s Remarks
Kimberly L. Colson, Ph.D., Product Manager, Bruker BioSpin Corporation
New Methods for NMR Analysis of Novel Natural Products and Synthetic Materials
Clemens Anklin, Ph.D., Vice President, Applications & Training, Bruker BioSpin Corporation
Our work focuses on the development of analytical tools to enable natural products chemists and synthetic chemists to rapidly analyze novel natural and synthetic materials, or analyze such materials in very small quantities. The recent advancements in NMR probe technology, sample delivery, experimental methods and enhanced integrated hyphenated techniques together with sophisticated software for chemical structure analysis positions chemists to meet current demands of the pharmaceutical discovery programs.
2:30 Natural Product Lead Discovery: Isolation and Precursor Directed Synthesis of Hits for Target-Based Screening Programs
Edmund Graziani, Ph.D., Principal Research Scientist I, Chemical & Screening
Sciences, Wyeth Research
Within the context of on-going screening efforts in our department, recent work highlighting three different approaches to generating chemical diversity in the service of identifying advanced hits for drug discovery programs will be presented. This will include a discussion of the preparation and biological activities of novel sulfur-containing derivatives of rapamycin by precursor directed biosynthesis, the evaluation of the historically useful macrolide antibiotics neutramycin for new analogs, and the isolation of new anti-inflammatory polyketides in a screen for inhibitors of MAPKAP kinase-2.
3:00 Development of a Second Generation Lipopeptide
Paul Brian, Ph.D., Scientist, Molecular Biology, Cubist Pharmaceuticals
Daptomycin is a first-in-class antibiotic marketed under the name Cubicin® (daptomycin for injection) approved by the FDA to treat skin and skin structure infections caused by Gram-positive pathogens. In order to discover a second generation lipopeptide antibiotic we have developed a program that combines combinatorial biosynthesis and chemical synthesis to generate novel daptomycin. A combination of module exchanges, subunit swaps and targeted changes within the daptomycin biosynthetic pathway has resulted in the production of lipopeptide combinatorial biosynthetic libraries. These have then been further modified by the semi-synthetic methods to increase the diversity of compounds that can be screened for improved activities. We will present and discuss some of the SAR data generated on these novel compounds.
3:30 Networking Refreshment Break, Poster and Exhibit Viewing
4:00 Natural Product-Like Chemical Space: Quest for Dissecting Signaling Networks by Small Molecules
Michael Prakesch, Ph.D., Senior Research Officer, Presenter;
Prabhat Arya, Ph.D., Senior Research Officer, Co-Author, Steacie Institute for
Molecular Sciences, National Research Council of Canada Adjunct Professor,
Biochemistry, McGill University, Ottawa Institute of Systems Biology, University
In the post-genomic chemical biology age, understanding (and dissecting) protein-protein interactions based signaling pathways by small-molecule probes is an exciting and challenging undertaking. We are developing novel approaches leading to high-throughput generation of alkaloid and flavonoid natural product-like polycyclic compounds having diverse 3D skeletal and stereochemical architectures. These compounds may prove to be very useful chemical probes because they are anticipated to occupy the chemical space currently being championed by bioactive natural products that are known for modulating protein-protein interactions-based signaling networks.
4:30 V-Atpase Inhibition: a Potential Cancer Target for Natural Products
John Beutler, Ph.D., Staff Scientist Department, Molecular Targets Development Program, National Cancer Institute
The salicylihalamides, lobatamides, oximidines, chondropsins, and palmerolides are marine and/or microbial natural products that potently inhibit cancer cell growth due to inhibition of vacuolar ATPase. Is this ubiquitous enzyme complex a valid target for cancer therapy, especially in melanoma or osteosarcoma? Can it be used to modulate cancer cell invasion and metastasis to bone sites? What subunits of V-ATPase are important for cancer-related processes and which for toxicity? This talk and the session will report investigations into these cutting-edge research topics.
5:00 Combinatorial Biosynthesis: New Opportunities for Natural Product Drug Discovery
Ben Shen, Ph.D., Charles M. Johnson Chair in Pharmacy, Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin – Madison
Combinatorial biosynthesis offers a promising alternative to prepare complex natural products and their analogs biosynthetically. The success of this approach depends critically on (1) the development of novel strategies for combinatorial manipulation of secondary metabolite biosynthesis gene clusters and (2) the continued discovery and characterization of biosynthetic machinery that catalyzes novel chemistry. Examples from our current study on various antitumor antibiotics will be presented to highlight the progress in this field with the emphasis on (1) novel chemistry involved in natural product biosynthesis and (2) application of combinatorial biosynthesis methods to microbial biosynthetic machinery to generate natural product structural diversity for drug discovery and development.
5:30 Chairperson’s Closing Remarks
5:40 Close of Conference
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