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Events Index - Abstracts and Proceedings - Achema 2000

 

2001 | Abstracts and Proceedings

Drug Discovery Technology 2000
- Full proceedings can be ordered online. Click Reports in: www.combichem.net/acatalog/

Keynote Address
The Future for Genomics
J. Craig Venter, Ph.D., President, Celera Genomics

The mapping and sequencing of the human genome combined with advances in genomic technologies has created a tremendous opportunity for drug discovery and development. On the discovery side, many of the newly discovered sequences represent novel targets for therapeutic intervention. On the development side, pharmacogenomics, proteomics and multiple nucleotide polymorphism mapping promises to supply some focus in terms of which targets are important, and the means of understanding and selecting patient populations for a given therapy. This presentation will describe where the world of genomics might be in the next ten years.

Keynote Address
The Drug Discovery Paradigm for the New Millennium
Frank Douglas, M.D., Ph.D., Head of Drug Innovation and Approval, Aventis Pharmaceuticals

Pharmaceutical companies must learn to succeed with the concept of Knowledge Management in the new millennium in order to survive in this competitive environment. A vast amount of information is being generated from the technology platforms of genomics, proteomics, automated high-throughput screening and combinatorial chemistry. The sciences of bioinformatics and chemoinformatics have both arisen from genomics/proteomics; chemoinformatics provides the architecture in which to formulate chemical diversity information. The concept of genetic variation arising from polymorphisms has birthed the science of pharmacogenomics, which poses a big challenge to the industry of how to precisely provide customized therapy to patients. In addition to real knowledge which we are managing, we can also create knowledge to manage.

 Aventis is a pioneer in the creation and use of predictive computational techniques to generate virtual knowledge. We are working with disease simulation models for asthma; designing virtual libraries of compounds with biased activities for a number of disease states; and using predictive software on virtual compounds to incorporate favorable metabolism, toxicity and absorption profiles. Thus, the use of Knowledge Management is critical to the manipulation of data from platform technologies, from pharmacogenomics studies and for virtual databases, and in the future, successful drugs will be closely linked to our successes with Knowledge Management.

Track 1: Genomics and Target Validation
Use of cDNA Databases to Identify and Develop Novel Therapeutic Candidates
Steve Ruben, Ph.D., Vice President of Research, Human Genome Sciences

The HGS functional genomics program includes many approaches directed toward discovery of therapeutic proteins. This has allowed our scientists to systematically evaluate thousands of full length genes for their potential as protein therapeutics. Currently two proteins and one gene therapy candidate are in clinical trials and many more activities are under evaluation for therapeutic potential.

Dissecting Signaling Pathways Using Functional Genomics
Donald G. Payan, M.D.

Using retroviruses to deliver conformationally constrained peptide libraries into mammalian cells is proving to be a rapid method to identify signaling pathway members whose function is altered by specific peptides, with the result that unique cellular responses can be regulated.

Data will be presented which will describe a complete functional genetic screen conducted using HTS in multiparameter FACS systems at Rigel. An analysis of the peptides and targets that they regulate will be reviewed in the context of signaling responses in mast cells following IgE binding to its high affinity receptor.

High-Throughput Gene Discovery and Validation
Sandra Glucksmann, Ph.D., Senior Director, Target Identification and Molecular Biology,
Millennium Pharmaceuticals, Inc.

Millennium integrates large-scale genetics, genomics, automation, informatics and drug discovery technologies to perform focused searches for disease-relevant targets and leads for drug development. Technologies developed by Millennium allow for simultaneous identification and investigation of thousands of new genes and their application in drug discovery. The drug targets are incorporated directly into test systems and used in the search for lead compounds. The presentation will offer some examples of the technologies and their application.

Integration of Genomics and Pharmacogenomics into Pharmaceutical R&D
Elliott Sigal, M.D., Ph.D., Senior Vice President, Early Discovery & Applied Technology,
Bristol-Myers Squibb

Multiple technologies have recently been developed to improve access to DNA information, to rapidly assess RNA or protein levels in relevant tissues and to validate function of potential new targets. The challenge facing pharmaceutical research units is one of effective integration of these new technologies in cost-effective ways that can have maximal effect on the discovery and development pipeline. Strategies will be described which utilize chemical probes earlier in the genomic process and which exploit model system genetics, gene-to-screen technologies and studies of mechanism of drug action.

The GABAB Receptor Heterodimer: Can Understanding Receptor Function at a Molecular Level Lead to the Development of New Drugs?
Fiona H. Marshall, Ph.D., Group Leader, Molecular Pharmacology, Glaxo Wellcome, United Kingdom

Baclofen was first used to treat spasticity in the early 70's, however, its molecular site of action, the GABAB receptor, has only recently been identified. Using the yeast two hybrid system to look for interacting proteins, we have identified a number of unusual properties in the function and signaling of this receptor which may ultimately lead to improved drug design.

G Protein-Coupled Receptors And CART"
Nigel R.A. Beeley, Ph.D., Vice President and Chief Chemical Officer, Arena Pharmaceuticals, Inc.

CART" (Constitutively Activated Receptor Technology) is a broad spectrum, screening technology based on a discrete set of gene-sequence mutations which, on expression of the corresponding G protein-coupled receptor (GPCR), stabilizes the active form whilst retaining the 3-D geometry of the ligand binding site. When applied to orphan GPCR's, the ensuing signal provides the means to screen libraries of compounds for inverse agonists, agonists and allosteric modulators without any knowledge of the endogenous ligand. Proof of principle using sub-types of 5HT receptors has resulted in the identification of novel, orally active, potential atypical anti-psychotic agents in vivo . Out of a large number of orphan receptors currently being examined in our research laboratories, one set has progressed to identification of a series of inverse agonists which show potential in vivo as orally active anti-obesity agents.

Track 2: Lead Generation and Optimization
Characterization of Small MW Inhibitors During the Drug Discovery Process Using Biacore Technology
Walter Huber, Ph.D., Section Head, F. Hoffmann-La Roche, Switzerland

We use SPR technology to study the binding of small MW compounds to proteins. Target proteins, such as HPPK, Aldolase and FVIIa are discussed in this presentation. Thermodynamic and kinetic constants, information on specific and unspecific binding as well as the insight into mechanistic aspects of the interaction serve as information for the selection and optimization of lead compounds.

OC144-093, a Novel Inhibitor of P-Glycoprotein-Mediated Multidrug Resistance (MDR): From First Synthesis to the Clinic in 18 Months
Michael J. Newman, Ph.D.

OC144-093 was discovered using OntoBLOCK" combinatorial chemistry technology with HTS. It is one of the most potent and selective MDR inhibitors to date. OC144-093 does not alter the PK of paclitaxel, protects rodents from paclitaxel toxicity in vivo and exhibits a desirable PK/safety profile in man. An integrated approach for highly efficient drug discovery by a small company will be presented.

Leveraging DiscoverWorks" in the Drug Discovery Process: Hit Identification to Lead
Optimization
Richard M. Soll, Ph.D., Vice President, Chemistry, 3-Dimensional Pharmaceuticals, Inc.

The DiscoverWorks" platform is a powerful enabling discovery engine that amplifies the DirectedDiversity® combinatorial chemistry process with high-throughput assay technology and structure-based drug design. In this presentation, we will discuss recent applications of DiscoverWorks" to diversity profiling, selection strategies, implementation of 3DP's drug-like probe libraries, hit identification, SAR generation, and the optimization process from billions of 3DP's synthetically accessible compounds. Applications to a number of molecular targets in cardiovascular disease and cancer will be presented.

Discovery of a Small Molecule Insulin Mimetic With Antidiabetic Activity
Bei Zhang, Ph.D., Senior Research Fellow, Merck Research Laboratories

Insulin elicits diverse biological responses by binding to its specific receptor. In a screen for small molecules that activates the human insulin receptor, a non-peptidyl fungal metabolite was identified by a team of scientists at Merck. The compound acted as an insulin mimetic in several biochemical and cellular assays and demonstrated antidiabetic activity in mice. Novel insulin receptor activators may potentially lead to new therapies for diabetes.

Discovery of Novel Antagonists for the CCR2 Receptor Utilizing the DuPont Pharmaceuticals
Research Labs "Discovery Engine®"
Wilna J. Moree, Ph.D., Senior Research Scientist, DuPont Pharmaceuticals Research Labs

The core process of DuPont Pharmaceuticals Research Labs, "The Discovery Engine®", has been deployed against a diverse range of receptor and enzyme targets in the areas of Lead Generation, Lead Evolution and Lead Optimization. A successful application of the Discovery

Engine® in the identification of novel series of antagonists for the CCR2 receptor will be presented. Profiling: The Hits, the Leads and the Screens
William E. Harte, Ph.D., Group Leader, CADD, Bristol-Myers Squibb Jonathan S. Mason, Ph.D.
Director, Structural Biology & Modeling, Bristol-Myers Squibb

The key to the lead identification and optimization process is the assessment and potential paths forward for both compounds and the screens themselves. Computational decision support approaches will be presented that tackle issues such as filtering, mining and analysis of both hits and screens.

Technology Workshops
E1: Application of FMAT" 8100 HTS System in High-Throughput Screening and Lead Optimization
Simon Pitchford, Ph.D., Associate Product Manager, Cellular Detection Systems, PE Biosystems

The FMAT" 8100 HTS System is a fluorescence-based assay system that incorporates a laser scanner and an optical detection system that provides a direct measurement of cellular or bead-based fluorescence on a well-to-well and an individual cell/bead basis. The use of this unique technology has allowed lead discovery researchers to address a broad application portfolio with a single detection platform. This workshop will include the presentation of experimental data from a wide variety of applications including recent developments in the area of cell viability. In addition, an example of how the FMAT system has been used in a screening operation will be presented.

E2: Advances in Laboratory Automation for Genomics and High-Throughput Screening
Moderator: Dan Roark, VP of Marketing and Sales, CCS Packard, Inc.
Speakers: Andrew Sheridan, Automation Coordinator, Whitehead Institute/MIT - Center for Genome Research
Kevin R. Oldenburg, Ph.D., Director, Biomolecular Screening, DuPont Pharmaceuticals

The advent of scale-up and throughput for genomics and drug discovery has increased the demand for more modular and configurable automated systems. Given the charge by the Human Genome Project to create cheap, reliable and high-throughput methods, the Whitehead Institute and CCS Packard collectively designed a genomic pipeline of PlateTrak systems. The pipeline is robust enough to undergo a twenty fold scale-up, taking the Center from 29,000 lanes to 580,000 lanes of high quality, low-cost sequence data per week. The evolution of the pipeline and the pluses and minuses of robotics systems will be discussed. CCS Packard also introduces a new standard of automation with the enhanced MiniTrak". A combination of new modular control electronics with the next generation TrakPREP Plus, providing a graphical drag & drop programming environment that automatically generates an optimized script. A demonstration focusing on the ease-of-use GUI and how integration of peripheral devices is done with the new MiniTrak".

E3: Novel Target and Toxicological Protein Biomarker Discovery with the SELDI ProteinChips System
Moderator: William Rich, Ph.D., President & CEO, Ciphergen Biosystems, Inc.
Speakers: Tina Morris, Ph.D., Senior Scientist, Human Genome Sciences, Theo Dare, M.Sc., Senior Clinical Pathologist, Glaxo Wellcome

Surface-Enhanced Laser Desorption/Ionization (SELDI) ProteinChip® technology allows proteins to be captured and analyzed directly on a chip surface. The System enables rapid, highly reproducible on-chip protein expression analysis from complex biological samples without prior purification, separation, tagging and amplification processes. The technology offers an excellent complement to gene expression studies employed in the search for disease markers and therapeutic targets. Because SELDI lends itself to the rapid screening of protein profiles in physiological fluids (serum, urine, CSF, etc.), it has proven effective in uncovering toxicological markers and monitoring drug clearance. Applications of the technology in the discovery and validation of differentially expressed targets and toxicological markers will be presented. New developments including the coupling of ProteinChip Arrays to a tandem mass spectrometer for confirmatory protein identification will also be discussed.

 E4: Performing High-Information Assays at Ultra High-Throughput on the Acumen Assay Explorer
John Cassells, Ph.D., Program Director, The Technology Partnership plc, United Kingdom

Acumen technology is available in both stand alone detectors and has integrated systems. It allows high-information to be obtained in UHTS primary screens. The Acumen technology combines the ability to detect sub-micron events within the simultaneous detection of fluorescence emission at multiple wavelengths. Data thresholding algorithms and multi-parameter data discrimination allow quantitative mix-and-read measurements to be performed on individual cells or beads in homogeneous assays. The technology can also be applied to miniaturization fluorescence and luminescence assays. Examples of assays performed with this system will be described.

F1: Advances in Fluorescence and Luminescence Technologies - Implications for Drug Screening and Target Identification
Anna Aherne, Ph.D., Product Applications Scientist, Molecular Devices Corporation

The FLIPR and FLIPR384 Systems have both been used for primary screening and SAR evaluations and measure changes in intracellular calcium or membrane potential from cells contained in 384- and 96-well plates (typical throughput is 20-150 plates/day). FLIPR384 also has expanded automation capabilities through its robot-line or stacker options. In addition, MDC offers a Chemiluminescence Imaging Plate Reader (CLIPR), a highly sensitive, high density, CCD-based luminometer system used for high-throughput screening and other drug discovery assays. This latter system offers the capability of working in plate densities up to and including 1536. Data will be presented on the use of both of these technologies in drug discovery.

F2: Imaging, Microarrays & Bioinformatics Advances from Hitachi Genetic Systems
Steve Lee, Ph.D., Director of R&D, Hitachi Genetic Systems

The mission of Hitachi Genetic Systems is to provide innovative, integrated instrumentation, software and reagent systems for detection and analysis of nucleic acids and proteins to facilitate scientific research and discovery. The three main areas of focus for the company are imaging, microarrays and bioinformatics. Our product line has undergone considerable expansion and includes a microarray workstation (SPBIO spotter, CRBIO reader and CHIPSpace"), a fluorescent scanner workstation (FMBIOII), UV/VIS spectrophotometers (GeneSpec I and III), CCD camera imaging systems (CCDBIO line), and software packages for 1D, 2D, proteomics and DNA analysis (TotalLab and DNASpace). Applications have been developed to target a total solution to gene identification, expression and protein analysis by providing innovative tools and software. Results of applications such as molecular beacons and differential display will be presented from both external laboratory end users and from our staff scientists.

 F3: Using ChemNavigator.com's iResearch System to Find and Buy Lead Expansion Compounds
Tad Hurst, Ph.D., Vice President and Chief Technical Officer, ChemNavigator.com

ChemNavigator.com provides the research community with a secure, reliable system for Internet-based searching and purchasing of compounds for lead optimization. Using ChemNavigator.com's iResearchTM System, members set customized filters, enter a search query, and order samples for testing. The searches return compounds that are known to be available and are similar to a lead compound or are direct analogs of a lead compound. The results are automatically grouped by similarity, easily allowing the member to browse hundreds of compounds in an organized fashion. Other data related, including patent and publication data, are displayed and used to make selection decisions. Compounds can also be selected based on vendor-specified parameters such as delivery time and re-supply status. The workshop will include an interactive demonstration focusing on the functionality of the iResearch System.

 F4: Liquid Handling Systems for High Speed Nanoliter Dispensing of Compounds into 96, 384 and 1536 Well Plates David W. Batey, Ph.D., Applications Manager, Robbins Scientific Corporation
A New Modular System for High Throughput Synthesis and Storage of Compounds in Glass James Stanchfield, Ph.D., Director, Business Development, Robbins Scientific Corporation
General Session Wednesday, August 16, 2000
1536 UHTS Integration
Mike Perenboom, National Sales Manager, CyBio, Inc.

UHTS in the drug discovery process has demonstrated the need for the integration of multiple components. Meeting this challenge, CyBio has become one of the leaders in system integration. The complex environment of research in life sciences not only demands reliable liquid-handling devices, it also requires clever solutions for analysis, transport and storage. Due to its modular concept, the design of the customer-tailored assembly is virtually unlimited. This seminar will describe CyBio's efforts in these areas. (Presentation will take place in the Breakfast Seminar Room)

Keynote Address
A New Paradigm in Chemical Library Generation
Steven V. Ley, FRS, Professor of Organic Chemistry, University of Cambridge, United Kingdom

The capability of high-throughput screening for potential drug candidates is placing ever increasing demands on methods for the fast and efficient generation of new chemical entities. In general, chemical libraries or arrays containing large numbers of compounds may be prepared on polymer supports or in solution. The advantages of polymer supported reactions and the benefits of easy monitoring of solution phase chemistry can be combined by using polymer supported reagents and scavengers. In this way we have devised multi-step reaction sequences, using only polymer supported species to effect the reactions, to afford new protocols for drug substance synthesis. The lecture will describe these new concepts and show applications to the rapid and efficient generation of novel chemical libraries in both linear and convergent formats.

Parallel Sessions
Track 1: Target and Compound Prioritization Using Gene Profiling and Differential Display Constructing Large-Scale Comprehensive Gene Expression Databases
Eric Eastman, Ph.D.

Gene Logic is using the combined power of open system gene expression technologies (READS" differential display) and microarrays (including the Affymetrix GeneChip") to develop large-scale expression databases. We are concentrating on the use of the GeneChip" to populate our GeneExpress databases and have determined thousands of RNA expression profiles from (1) normal and diseased mammalian tissues; (2) experimentally manipulated animals and cell lines; and (3) tissues and cells treated with a diversity of known pharmacologic and toxicologic agents. To complement these closed system approaches, our READS" differential display technique allows us to confirm such data as well as discover novel genes. The technical issues in generating and benchmarking such large expression databases will be presented. In addition, the biological relevance of data generated from this approach will be illustrated by case studies.

Gene Expression Profiling: Its Application in Drug Discovery and Clinical Development
Eugene L. Brown, Ph.D., Director, Expression Profiling Sciences, Genetics Institute, Wyeth-Ayerst Research

There are now a variety of methods for simultaneously measuring many, if not all, of the mRNA species in cells and tissues. These gene expression profiling techniques, along with a range of statistical experimental design and analysis methodologies, are beginning to have a great impact on drug discovery as we begin the new millennium. This presentation will show several examples of the application of gene expression profiling to target identification and surrogate marker discovery in clinical development.

Gene Expression Analysis for Drug Target Discovery and Toxicology
Roland Somogyi, Ph.D., Director, Neurobiology, Incyte Pharmaceuticals, Inc.

High-throughput gene expression profiling allows us to monitor the activity of complex gene regulatory networks. Understanding these networks will provide us with new drug targets and early indicators of toxic drug side effects. The key to a successful application of these technologies lies in properly matching experi-mental design with data mining and predictive modeling methods.

Using In Silico Metabolism in the Early Drug Discovery Process: Methods and Pragmatic Applications
Scott Boyer, Ph.D., Senior Research Scientist, Chemical Computing Group, AstraZeneca, United Kingdom

Metabolic instability is a very common limiting factor in rapidly obtaining acceptable ADME properties early in the drug discovery process. Synthetic efforts to address metabolic instability are enhanced greatly by metabolite identification, however rapid and routine access to this information is often very limited. This presentation will focus on the development of computational methods that give information not only on possible metabolism routes, but probable metabolism routes in order to help focus synthetic efforts.

Application of Microdialysis and LC-MS/MS for High-Throughput Bioavailability and CNS Penetration in Drug Discovery
Mohammed S. Alavijeh, Ph.D., Team Leader, Discovery Drug Disposition, Aventis Pharmaceuticals,United Kingdom

Synthesis of large chemical libraries has increased the number of NCEs reaching the lead optimization stage where pharmacokinetic parameters are key to the selection process. The in vivo and bioanalysis phases have increasingly become the rate limiting steps. This presentation will focus on the approaches implemented to improve and accelerate throughput, circumventing limitations in relation to the optimization and selection of CNS compounds.

The Utility of Combining Physicochemical and In Vitro Physiological Properties of Drug Compounds for Estimating In Vivo Oral Bioavailability - A Case Study Gary W. Caldwell, Ph.D., Research Fellow, The R.W. Johnson Pharmaceutical Research Institute

This presentation will demonstrate how liberation, absorption and metabolism rates can be classified as high/low based on physicochemical (aqueous solubilities and chemical stabilities) and in vitro physiological assays (absorption - human Caco-2 cell lines, and metabolism - rates of drug biotransformation obtained from human hepatocyte or microsomal suspensions). Several case studies will be presented to illustrate the advantages and disadvantages of the procedure.

High-Throughput Approaches to Pre-ADME Studies as a Tool for the Prioritization of Lead Compounds
Ilona Kariv, Ph.D., Principal Research Scientist, Leads Discovery, DuPont Pharmaceuticals

This presentation will focus on the practical aspects of developing the following pre-ADME HTS screens: (A) compound binding to serum proteins; (B) in vitro metabolism studies of two predominant cytochromes P450 enzymes, 3A4 and 2D6, as an indication of compound metabolic stability; and (C) identification of compounds that are substrates for efflux pumps, which in conjunction with the data obtained from absorption studies using in vitro validated systems, such as CACO-2 cell line, provides a tool to assess compound bioavailability. The advantages and limitations of each approach will be discussed.

Expediting Drug Candidate Selection: Integration of Computational Analysis in Toxicologic Assessment
Stephen K. Durham, Ph.D.

The global pharmaceutical business environment necessitates the early and successful selection of drug candidates. Favorable characteristics from a biopharmaceutic, ADME and preclinical drug safety perspective should be "built into" the desired drug candidate molecule. Toxicologic liabilities should be determined by a multivariate in silico , in vitro and in vivo analysis.

This presentation will focus on the aggressive integration of structure- and rule-based computational testing methodologies. In silico analysis coupled with post-computational validation via predictive in vitro assays and emerging molecular technologies are progressive avenues important in the selection process.

The Asthma PhysioLab: A Software Environment Designed to Simulate Asthma Disease Processes for Drug Discovery and Development
Robert J. Dinerstein, M.D., Ph.D., Senior Research Scientist, Aventis Pharmaceuticals
Thomas S. Paterson, Ph.D., Chief Scientific Officer, Entelos, Inc.

Pharmaceutical research organizations are seeking therapies for increasingly complex and intractable diseases. These efforts are complicated by an inundation of genomic, biological and clinical data. The PhysioLab concept for disease simulation was developed in order to facilitate hypothesis generation and decision-making in the face of these challenges. A PhysioLab model has been constructed for asthma, a disease of the airways involving physiological, immunological and biochemical changes that lead to a characteristic chronic inflammation and episodic bronchoconstriction. The Asthma PhysioLab simulates these processes by integrating the qualitative clinical data from more than 1,500 references and the input from eight renowned consultants. This presentation will describe the principles and structure of the Asthma PhysioLab, as well as specific examples of results obtained with it.

Coupling Genomics to Drug Design
David Bailey, Ph.D., Chief Executive Officer, De Novo Pharmaceuticals, United Kingdom

The sequencing of the entire Human Genome, a first draft of which is due to appear in the public domain this year, will provide at least 3,000 new therapeutic targets for the pharmaceutical industry. This presentation will outline how this avalanche of genomic information can be rapidly utilized in silico in the race to generate new lead compounds for these novel targets.

Knowledge-Based Approaches to Protein Structure and Function Uses in Drug Discovery
Mark Swindells, Ph.D.

A vast number of gene and protein sequences continue to be identified by the Human Genome Project. The real down-stream value from these endeavours will be realized only when each protein's structure and function can be determined. Inpharmatica has developed a formidable relational database known as the BiopendiumTM which brings together information on sequence, structure and function relationships for all gene/protein products. Information derived from the Biopendium has contributed to the discovery of novel targets for the identification of antibiotics with unique mechanisms of action and the discovery of new drugs to treat conditions such as Inflammatory Bowel Disease.

Track 2: Combinatorial and Medicinal Chemistry Interface
The Integration of Novel Lead Discovery Technologies: Closed Loop and Non-Combinatorial Chemistry Action Jeremy Everett, Ph.D., Director of Medicinal Technologies, Pfizer, Inc., United Kingdom

This presentation will cover the way in which chemoinformatics, library chemistry, compound storage and retrieval, ultra HTS and information technologies have been integrated so as to impact on the efficiency of lead discovery at Sandwich, UK. Our aim has been to achieve an efficient "closed loop" mode of lead discovery by exploiting the use of virtual library technology and non-combinatorial chemistry.

Structure-Based Drug Design of HMR3480/VX-740: A Potent, Orally Available Inhibitor of the Interleuken-1ß Converting Enzyme (ICE)
Michael D. Mullican, Ph.D., Principal Investigator, Vertex Pharmaceuticals, Inc.

The discovery of HMR3480/VX-740, a potent, orally available inhibitor of ICE was achieved through integrated drug design involving: (1) Structure-based design of peptidomimetic scaffolds utilizing the high-resolution crystal structure of ICE/tetrapeptide inhibitor co-complex; (2) Rapid solid phase parallel synthesis to optimize enzyme and cell potency; and (3) Novel prodrug design to improve oral availability. HMR3480/VX-740 is the first ICE inhibitor to be studied in humans and is currently in a Phase II clinical trial for rheumatoid arthritis.

Streamlining Chemical Library Synthesis and Structural Validation: Generation and Advancement of Leads Bruce C. Hamper, Ph.D.

A combination of solid and solution phase techniques have been developed for the streamlined preparation of targeted compounds. A PlateView system, which can be viewed from a web browser, facilitates the archival and analysis of analytical data (HPLC, LCMS, NMR, etc.) associated with individual compounds from these libraries. Using combinatorial analytical tools, sets or libraries of compounds can be evaluated for structural confirmation and purity.

Design of Mixture Libraries Targeted at G Protein-Coupled Receptors
Chris Willoughby, Ph.D., Research Fellow, Merck & Co., Inc.

Ligands for G protein-coupled receptors represent a significant portion of marketed drugs. Using combinatorial libraries, we have discovered several classes of compounds that selectively bind to various G protein-coupled receptors. This presentation will focus on the design of libraries targeted at serotonin receptors. From these libraries selective ligands have been identified for several receptor targets. These molecules have become the starting point for more focused medicinal chemistry efforts.

Confocal Fluorescence Detection Technology in Pharmaceutical Drug Discovery
Manfred Auer, Ph.D., Research Program Head, Novartis, Austria

Miniaturization is one of the key technology concepts of current high-throughput screening to meet the future needs of fast and cost-effective drug discovery. Multicolor, confocal fluorescence spectroscopic and scanning techniques are amongst the most suitable methods enabling mechanism-based screening on miniaturized assay formats in homogeneous solution and on the solid phase. The current status of assay development based on fluorescence correlation spectroscopy (FCS), fluorescence intensity distribution analysis (FIDA) and confocal nanoscanning will be reviewed.

Miniaturization Technologies for High-Throughput Biology
Peter Coassin, Vice President, Instrumentation R&D, Aurora Biosciences Corporation

This talk will summarize Aurora's strategy to integrate biology with miniaturized automation to enable high-throughput screening and biological research. Specific components of the process will be described, including microfluidics, detection, sample handling and bioassay technology amenable to high density formats. Results from ultra high-throughput (e.g. 100K samples/day) assays will be presented. The implications of the increased productivity these systems allow for determining the functions of genes will be discussed.

Gene to Lead Strategies in the Genomic Age
Paul Negulescu, Ph.D., Vice President, Cell Biology, Aurora Biosciences Corporation

With sequencing of the human genome nearly complete, drug discovery has entered a phase where parallel analysis of gene expression and function is an essential approach for identifying both potential drug targets and chemical modulators of those targets. While gene expression can be studied using oligonucleotide array methodologies, detection of gene function requires alternative approaches. The presentation will describe strategies that employ functional assays and high density screening arrays for most target classes. The assay platforms are based on cassettable biosensors for various types of regulatory genes. The biosensors are designed to enable rapid assay development and are amenable to ultra-high throughput screening of chemical libraries such that assays for entire classes of genomic targets are now feasible. The implications of an industrialized, process-driven approach for biological research and drug discovery will be discussed.

Submicrolitre Assays on Plastic LabCards: OASIS"
Sharat Singh, Ph.D., Director, Advanced Technologies, ACLARA Biosciences

Aclara Biosciences has developed a novel 96-well submicrolitre assay system called OASIS". The open architecture of OASIS" microfluidic LabCard offers a unique solution to the fundamental problem of evaporation in submicrolitre reactions. Aclara's system allows multiple additions of reagents including stop reagents using nanovolume dispensers. The presentation will provide experimental data showing ease of reformatting existing homogenous assays to submicrolitre OASIS" format using existing instrumentation. Implementation of 200 nanolitre 96-well assay screening system using existing liquid handling systems and commercial plate readers will be illustrated by examples from two assay classes: Enzymatic and Receptor binding.

Miniaturized Ultra High-Throughput Screening Strategies
Andrew J. Pope, D.Phil.

Recent developments in fluorescence instrumentation and robotic/liquid handling hardware are producing highly efficient, fast, miniaturized and information rich screening systems capable of supporting the lead discovery process in the post Genomic, post Combi-Chem era. This talk will focus on the application of a wide range of different fluorescent techniques, including conventional as well as single molecule approaches, to deliver the needs of ultra HTS for a wide range of therapeutic target types. In addition, the direct applicability of these approaches to non-HTS activities such as early ADME and SAR/mechanistic characterization of chemical leads will be exemplified.

High-Throughput Screening of Ion Channels Using Novel Fluorescence TechniquesGregory J.
Kaczoroski, Ph.D., Senior Director, Department of Membrane Biochemistry and Biophysics, Merck Research Laboratories

Establishing high-throughput functional ion channel screening assays is critical for successful drug development. To this end, we have used proprietary fluorescence dyes developed by Aurora Biosciences Corporation to monitor membrane potential in cells where expression of maxi-K channels control resting potential; channel blockers cause cell depolarization and this configuration can be applied in high capacity screening protocols. Such approaches could be generalized for developing other types of ion channel screens.

A Statistical Approach for Evaluating HTS Assays
Ji-Hu Zhang, Ph.D., Principal Scientist, DuPont Pharmaceuticals

A simple but effective statistical parameter was created for use in evaluation and validation of HTS assays. This parameter is superior to the frequently used signal-to-noise or signal-to-background ratios in determining the assay quality in HTS. Applications of this statistical approach in HTS assay validation and in primary screening data analysis will also be presented.

Strategy and Serendipity in the Discovery of Calcimimetics
Edward F. Nemeth, Ph.D., Chief Scientific Officer, NPS Pharmaceuticals, Inc.

Calcimimetics are first in class compounds acting on a unique receptor and are in late-stage clinical development for the treatment of hyperparathyroidism. The preclinical cycle time reviewed in this case history is remarkable for its brevity despite the absence of a cloned target, high-throughput screen, or any structural information derived from the receptor's ligand (calcium ions). Certain features of the drug discovery strategy which facilitated rapid entry into the clinic are described. Some of these lessons might be applied generally to reduce the technical uncertainties of the drug discovery process.

Drug Discovery Case Histories: SYMLIN" (Pramlintide Acetate) and AC2993 (Synthetic Exendin-4)
Andrew Young, M.D., Ph.D., Vice President of Research, Amylin Pharmaceuticals, Inc.

Both SYMLIN and AC2993 are peptide drug candidates that share certain glucoregulatory actions of human hormones. SYMLIN is a synthetic, modified version of the human hormone amylin. AC2993 is a synthetic version of exendin-4, a peptide first isolated from the salivary secretions of Heloderma suspectum that shares some of the biological actions of the human hormone, glucagon-like peptide-1 (GLP-1). The pathways from discovery to clinical development for SYMLIN and AC2993 have been quite different, and exemplify many aspects of development of peptide drug candidates.

Discovery and Development of Remicade for Inflammatory Disease
Thomas F. Schaible, Ph.D., Senior Director, Immunology Medical Affairs, Centocor

In chronic inflammatory disorders, such as rheumatoid arthritis (RA) and Crohn's disease (CD), the cytokine, tumor necrosis factor alpha (TNF, plays a pivotal role in the inflammatory process. REMICADE (infliximab) is an anti-TNF monoclonal antibody that neutralizes the biologic activity of TNF with high affinity, avidity and specificity. REMICADE is currently registered in the US for CD and RA and in Europe for CD. This presentation will focus on some of the similarities and differences between the clinical development programs in RA and CD and lessons learned.

Discovery and Development of Relenza: An Anti-Influenza Therapy
Eddie Blair, Ph.D., Group Leader, Predictive Medicines Group, Glaxo Wellcome, United Kingdom

Determination of the atomic structure of the influenza virus neuraminidase enzyme greatly facilitated the design and development of the potent anti-influenza compound Relenza. The structural information has also been of value in rationalizing the impact of single amino acid changes in the active site of the neuraminidase in terms of both enzymatic activity and alterations in sensitivity to inhibition by Relenza.

The Discovery and Development of Celecoxib: A COX-2 Specific Inhibitor
Karen Seibert, Ph.D., Director and Senior Fellow, Searle

A wealth of data obtained since 1991 has shown that in animals COX-2 is expressed in inflamed tissues, is regulated by glucocorticoids and appears to be the target for the therapeutic effects of the NSAIDs; in contrast, inhibition of COX-1 is likely to account for the toxic side effects associated with long term NSAID use. Work at Searle has led to the discovery and development of COX-2 specific inhibitors, the first of which is celecoxib. Preclinically, celecoxib is a highly effective treatment in models of arthritis, inflammation and pain, with improved safety compared to conventional NSAIDs. Additionally, preclinical evidence suggests a role for COX-2 in tumorigenesis and neural degeneration. Therefore, in addition to their utility in the pain and inflammation of arthritis, agents such as celecoxib may offer new therapeutic opportunities, such as in the prevention of cancer.

Case Study of Xenical: An Anti-Obesity Drug
Jonathan Hauptman, M.D., Director of Global Drug Development - Metabolic Diseases, Hoffmann-La Roche, Inc.

The development of Xenical as a novel treatment for obesity represents a collaboration of many different scientific and medical disciplines over a 30 year period of time. Research into the inhibition of fat and cholesterol absorption as an approach to lipid lowering was refocused towards the treatment of obesity as it became clear that there were major medical consequences from being even mildly obese and that there was an unmet medical need for new pharmacological therapies.

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