CHI - Drug Discovery Japan

Drug Discovery Japan brings together leading researchers from around the world to discuss their experiences with many aspects of the drug discovery process from bioinformatics, proteomics, target identification and validation, to screening of combinatorial libraries, structure-based drug design, and ADME/Tox studies.
Reasons to attend . . .

Topics For Discussion:
Biotech Business Strategy
Proteomics
Bioinformatics
Target Identification and Validation
ADME/Tox/Toxicogenomics
Library Design, Chemoinformatics, and Structure-Based Drug Design
High-Throughput Organic Synthesis
Screening Technologies and Results

Speakers
Dr. Alex Abuin, Lexicon Genetics Incorporated
Dr. Tom Barnett, Karo Bio USA, Inc.
Dr. Armen M. Boldi, ChemRx Advanced Technologies, Inc.
Dr. Robert Brown, Accelrys, Inc.
Dr. Alexey V. Eliseev, State University of New York at Buffalo and Therascope AG
Prof. Kimito Funatsu, Toyohashi University of Technology
Dr. Toshio Furuya, PharmaDesign, Inc. and University of Tokyo
Mr. Martin Gollery, TimeLogic Corporation
Dr. Osman F. Güner, Accelrys, Inc.
Dr. John Harrington, Athersys, Inc.
Dr. Toru Horie, Dethree Research Laboratories
Dr. Moncef Jendoubi, Milagen, Inc.
Dr. Harren Jhoti, Astex Technology Ltd.
Dr. Hiroaki Kitano, Kitano Symbiotic Systems Project
Prof. Gerhard Klebe, University of Marburg
Dr. Kerstin Klein, GeneData AG
Dr. Robert Klein, Deltagen, Inc.
Mr. Sean R. Klopfenstein, Procter & Gamble Pharmaceuticals
Prof. Robert Kneller, University of Tokyo
Dr. Akira Komoriya, OncoImmunin, Inc.
Dr. Andreas Köpke, WITA Proteomics AG
Dr. Hidehito Kotani, Banyu Tsukuba Research Institute
Dr. Albert P. Li, In Vitro Technologies, Inc.
Dr. Graeme Martin, Telik, Inc.
Dr. Hisakazu Mihara, Tokyo Institute of Technology
Dr. Kiyoshi Nokihara, Shimadzu Scientific Research Inc.
Dr. Andrew Parkinson, XenoTech LLC
Dr. Kal Ramnarayan, Structural Bioinformatics, Inc.
Dr. Frans L. Stassen, Suntory Pharmaceutical Research Laboratories LLC
Prof. Yuichi Sugiyama, University of Tokyo
Prof. Takashi Takahashi, Tokyo Institute of Technology
Dr. Michael H. Tarbit, Camitro UK Ltd.
Dr. Deepak Thakkar, Silicon Genetics
Dr. Flossie Wong-Staal, Immusol, Inc.
Dr. Toru Yao, Institute of Physical & Chemical Research (RIKEN) and Toin Yokohama University
Mr. Ali R. Zareh, Corimbia Inc.

8:30 Chairperson's Opening Comments
Prof. Robert Kneller, Department of Intellectual Property, Research Center for Advanced Science and Technology, University of Tokyo

8:40 Intellectual Property and Technology Transfer from Universities and Government Research Institutes
Prof. Robert Kneller
Numerous restrictions on R&D contracts involving Japanese national universities create significant obstacles to university-industry cooperation in biotech. In addition, the system of ownership and transfer of IPR creates weak incentives to develop most university biotech discoveries. Finally, social and institutional factors, including the tradition of lifetime employment, weak venture management, noncompetitive promotion in universities, ineffective peer review, and over-reliance by Japanese pharmaceutical companies on in-house R&D, also degrade the environment for productive university-industry cooperation. Nevertheless, interest among university faculty in forming venture companies is strong, capital generally is available, and legal reforms have made it easier for national university faculty to participate in biotech start-ups and in consultative/management relationships with pharmaceutical companies. For foreign investors, formation of Japanese biotech spin-offs offers a promising way to tap the energy and talent in university laboratories, although barriers remain.

9:10 A New Drug Discovery Business Model in the United States
Dr. Frans L. Stassen, President and Chief Executive Officer, Suntory Pharmaceutical Research Laboratories LLC
During the last decade, a number of Japanese pharmaceutical companies, including Chugai, Eisai, Shionogi, and Tanabe, have expanded their drug discovery operations by establishing wholly owned subsidiaries in the United States and Europe. However, Suntory Ltd., a leading Japanese corporation with a diverse product line including pharmaceuticals, has pioneered a different strategy to capitalize on the entrepreneurial environment in the United States. Suntory Ltd. has established a majority-owned biopharmaceutical company, Suntory Pharmaceutical Research Laboratories LLC (SPRL), with the mission of providing Suntory Ltd. with preclinical drug candidates. SPRL is an arms-length company with a business model similar to that of venture capital-backed biopharmaceutical companies. Its current therapeutic focus is cardiovascular and immune disorders, with considerable emphasis on structure-based drug design as its primary engine for lead generation and optimization. An overview of the company, its direction, objectives, and technologies will be discussed.

10:45 Chairperson's Comments
Dr. Kiyoshi Nokihara, Chief Scientist and Founder, Shimadzu Scientific Research Inc.

10:50 Development of Peptide Chips, Array Displays of Designed Synthetic Peptides
Dr. Kiyoshi Nokihara
In the last decade DNA arrays have become well established and widely used for biomedical research. Consequently, protein arrays will be the next target for biochip development. We have developed a unique design concept that furnishes high-quality synthetic peptides immobilized on chips. The advantages are a very flexible design in which immobilized molecules are not required in large numbers and are produced using synthetic methods that are quite well established.

11:20 High-Resolution Proteomics: New Solutions for Target and Drug Validation in Human Diseases
Dr. Andreas Köpke, Chief Executive Officer, WITA Proteomics AG
Proteomics holds the potential to revolutionize the drug discovery process. 2DE and in particular the ease of use of IPG technology have lowered the entry barrier for studying proteins associated with a particular disease state and have enabled higher throughput analysis of human samples on the proteome level. The ability to correctly identify proteins and their relative abundance changes is critically linked to resolution. With a threefold improvement in resolution, up to 10,000 spots per gel resolving power, the NEPHGE technique is well positioned to validate protein targets, validate drug efficacy, and determine the toxicological properties of candidate drugs. Case studies utilizing WITA's technology in determining changes in the proteome have been successfully employed to study schizophrenia, fertility, and liver toxicity; selected examples will be presented.

11:50 Technology Development and Its Impact on in Silico Biology
Dr. Kal Ramnarayan, Vice President and Chief Scientific Officer, Structural Bioinformatics, Inc.
With the completion of the mapping of the human genome in 2001, efforts are under way to understand the functional role of the gene products-i.e., proteins involved in biological pathways and human diseases-and to exploit their roles in order to derive protein therapeutics as well as protein-based drugs. Protein structure is a key component of this next revolution in the "post-genomic" era and will be critical for in silico experimental design. Improvements in quality, availability, and utility of large-scale protein structural information are enabling rational design in the life sciences, having particular impact on drug discovery and optimization. New computational methodologies now yield modeled structures that are quantitatively comparable with X-ray crystal structures, at a fraction of the cost in many cases. In this presentation, we will discuss the development of certain technologies that will impact in silico biology in the pharmaceutical and biotechnology industries.

1:30 Chairperson's Comments
Dr. Hiroaki Kitano, Chief Executive Officer, Kitano Symbiotic Systems Project

1:35 Bioinformatics and Systems Biology in the Post-genome Era
Dr. Toru Yao, Consultant, Genomic Sciences Center, Institute of Physical & Chemical Research (RIKEN); and Visiting Professor, Toin Yokohama University
Bioinformatics plays a very important role in not only genome sequence analysis, gene finding, or gene annotation but also comparative genomics, structural genomics, and functional genomics. Bioinformatics handles a lot of data from those activities and extracts useful information for the understanding of biological or medical phenomena. We should proceed, however, to understand whole schemes of many biological processes by incorporating pieces of knowledge. Systems biology aims to understand many physiological or pathological processes as whole systems. Various movements are now emerging in these fields. I will present an overview of those activities in the world and especially in Japan.

2:05 Modeling Issues in Cellular Systems for Systems Biology
Dr. Hiroaki Kitano
With rapid progress in molecular biology, particularly high-throughput genomics and proteomics, our knowledge on components of the biological systems has significantly enlarged. The obvious next step is to understand biological systems at the system-level. Attempts gain system-level understanding of biological systems has been a recurrent theme since Norbert Wiener. However, for the first time in the history that there are opportunities to establish system-level understanding grounded on the molecular-level of understanding. This talk provides general perspectives on systems biology, current status, research issues, and provides in-depth description of some of the projects the speaker is running, such as software infrastructure projects (systems biology workbench and systems biology mark-up language (SBML)), and system-level research on yeast and C. elegans. In addition, systeome projects are briefly described. Systeome is an assembly of all system profile information analogous to genome and proteome.

2:35 Application of in Silico Functional Genomics for the Drug Discovery Process in the Post-genomics Era
Dr. Kerstin Klein, Scientific Marketing Specialist, GeneData AG
With the onset of high-throughput technologies for the molecular analysis of biological systems, life science has entered a new era. For the first time in the history of biology, the bottleneck of pharmaceutical research aiming at the understanding of biological processes in tissues and individual cells has moved from mere data acquisition to the analysis and biological interpretation of these data. To overcome this problem we have developed a comprehensive suite of integrated software systems to tackle the typical, technology-specific problems in data-quality assessment and data mining of genome, transcriptome, proteome, metabolome, and high-throughput screening data. The presented case study highlights the major improvement in discovery efficiency gained by the integrated analysis of both genome-sequence and gene-expression data.

3:45 Statistical Intelligence: Key to Effective Analysis of High-Density Microarray Data
Mr. Ali R. Zareh, Vice President, Business Development, Corimbia Inc.
Gene expression profiling experiments are typically complex studies involving a number of variables. Effective analysis of the data obtained from such studies requires an understanding of the sources contributing to the variations in the data, e.g., experimental design, sample processing, and detection technology. We will discuss the use of statistical intelligence and exploiting historical data samples to more effectively identify and filter the noise in the data and identify the biologically important changes, particularly for analysis of high-density oligo microarray data.

4:15 Proteomics in the 21st Century
Dr. Cédric Loiret-Bernal, Chief Executive Officer, GeneProt, Inc.

4:45 High-Throughput, Enterprise-Level, Scalable Informatics Products and Services for the Post-genomics Era
Dr. Deepak Thakkar, Senior Director, Marketing, Silicon Genetics
The completion of the human genome project has resulted in the systematic use of genomic technologies and resulting data in traditional drug discovery processes. Genomic tools ranging from ultrahigh-density oligonucleotide and cDNA microarrays for gene expression analysis to low-to-medium density antibody arrays for proteome analysis are in routine use in laboratories worldwide. These tools have the potential of unlocking critical information pathways, facilitating the pharmaceutical discovery process. The millions of data points created by the use of these technologies can be unraveled by powerful, validated, high-quality informatics solutions. Silicon Genetics™ has developed a suite of such scalable products addressing these high-density informatics demands, and highlights of this technology will be presented in detail. Silicon Genetics' enterprise-level integrated informatics solution facilitates the drug discovery process by providing unique, intuitive solutions addressing the data management and mining bottleneck from desktop all the way to high-powered server level. Silicon Genetics' GeneSpring™, GeNet™, and MetaMine™ solutions are being used by over 4,000 scientists globally, and several case studies demonstrating the use of our proprietary technology portfolio for gene identification, pathway prediction, large data set comparison, data sharing, etc. will be presented.

8:30 Chairperson's Comments
Dr. Flossie Wong-Staal, Vice President of Genomics, Immusol, Inc.

8:35 Activation of Endogenous Genes using RAGE: Applications in Drug Screening
Dr. John Harrington, Executive Vice President & Chief Scientific Officer, Athersys, Inc.
The RAGE (Random Activation of Gene Expression) technology can be used to generate comprehensive protein expression libraries for use in high-throughput screening projects to identify proteins that function in specific biological pathways. RAGE libraries can be constructed in a variety of cell types, including cell lines engineered for use in specific functional screens. Once a protein that exhibits a desired biological characteristic has been detected, the gene encoding such protein can be rapidly identified. As a result, structural and functional screening of an entire genome can be achieved in a rapid and efficient manner. This allows the identification of tightly regulated, potentially medically relevant genes that are often associated with important biological activities, which might otherwise be missed using conventional cDNA or shotgun sequencing approaches.

9:05 Large-Scale in Vivo Target Validation for Drug Discovery
Dr. Alex Abuin, Director, Genetic Technologies, Lexicon Genetics Incorporated
The large number of novel genes arising from the sequencing of the human genome presents the pharmaceutical and biotechnology industries with an extensive pool of potential new drug targets and therapeutics. Information about gene function, however, has become a major rate-limiting step in the drug discovery process. Drug development programs that are supported by solid biology will require the rapid, large-scale analysis of mammalian gene function. In order to address this need, Lexicon has established the Genome5000 program, a genomewide in vivo functional discovery program designed to determine the physiologic functions of 5,000 genes over five years. We are using both gene trapping and gene targeting technologies for the large-scale generation of mice with mutations in pharmaceutically relevant genes such as receptors, ion channels, secreted proteins, and key enzymes such as proteases and kinases. Through Lexicon's phenotypic analysis program, these mutant mice are subjected to a comprehensive battery of diagnostic tests including radiography, hematology, neurology, histology, pathology, and immunology, and many other data types are recorded. Our analysis includes comparisons between wild-type, heterozygous, and homozygous mice within each line and with respect to the total population. All of the pedigree and physiological data are collected into a comprehensive relational database. In turn, this database can be queried at all levels (from raw data for every individual mouse up to summary evaluations of specific mutant lines) allowing the efficient assignment of gene function.

9:35 Antibiomix: A Paradigm Shift in High-Throughput Target Validation
Dr. Moncef Jendoubi, Founder and President, Milagen, Inc.
Antibiomix is the process of generating antibodies to all proteins of any living organisms. Milagen produces a large number of high-affinity antibodies (>5,000 per month) to human gene products. Milagen currently has generated 40,000 antibodies to human proteins and will have >70,000 antibodies by the end of 2002. Antibiomix applications include antibody arrays, protein arrays, and validation of disease targets for diagnostics and therapeutics.

10:45 Combining in Vivo Mammalian Gene Function with Genomewide Gene Expression Analysis to Select the Best New Drug Targets
Dr. Robert Klein, Vice President, Technology Development, Deltagen, Inc.
Genome sequencing efforts have identified thousands of genes with no known function representing potential new drug targets for the pharmaceutical industry. The challenge is to identify which targets have therapeutic potential early in the drug discovery process. We have focused on assigning in vivo mammalian function to novel members of gene families representing drugable targets, including GPCRs, ion channels, nuclear hormone receptors, kinases, phosphatases, and others utilizing the preferred mammalian model organism, the mouse knockout model. We are currently generating, on average, one new phenotypically characterized gene knockout every day. Following extensive phenotypic analysis, including pathological, immunological, cardiovascular, metabolic, and behavioral tests, the data is organized into a user friendly, web based, searchable database. We are extending this information through system- and genome-wide gene expression analysis. This dataset provides direct target validation about mammalian gene families most relevant to drug discovery. Examples demonstrating the strength of our approach for identifying new drug targets will be presented.

11:15 Inverse Genomics™ for Drug Target Validation
Dr. Flossie Wong-Staal, Immusol
Immusol uses a proprietary technology platform called Inverse Genomics™ to identify and functionally validate therapeutic drug targets in the areas of cancer, neurodegenerative diseases, allergy/inflammation, obesity/diabetes, and infectious diseases. This technology starts with a medically important function and works backward to identify the relevant gene sequences involved specifically in that function. Inverse Genomics™ uses a combinatorial library of over 10 million unique gene-inactivating hairpin ribozymes. The substrate-binding sequences in this library have been randomized so that the ribozyme library has the potential to target any cellular RNA. Once introduced into a disease-based cell system, a ribozyme will recognize and cleave unique RNA transcripts, thereby preventing translation of various proteins. Using this Inverse Genomics™ system, we recover the ribozymes from cells exhibiting an altered, desired phenotype. Based on the ribozyme's substrate-binding sequence, a biologically relevant target gene, which is linked to the therapeutic effect, is identified. Using Inverse Genomics™, Immusol has developed a portfolio of over 50 biologically validated drug targets, including a regulator of BRCA 1 expression and co-factors of HCV internal ribosome entry site-mediated translation.

1:00 Chairperson's Comments
Dr. Albert P. Li, Chief Scientific Officer, In Vitro Technologies, Inc.

1:05 Screening Systems for Drug Transporters: Use of Cells and Membrane Vesicles Prepared from Tissues and Transporter cDNA Transfected Cells
Prof. Yuichi Sugiyama, Chair, Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo
Functions of influx and efflux transporters have to be evaluated separately. Isolated cells, cultured cells, and cDNA transfected cells can be used for evaluating the drug influx transporter activities. Membrane vesicles prepared from tissues and cDNA transfected cells can be used for evaluating the ATP-dependent efflux transporters such as MDR and MRP. Importance of the use of double transfectants (simultaneous expression of influx and efflux transporters) will also be shown.

1:35 Cryopreserved Human Hepatocytes for ADME-Tox Screening Assays
Dr. Albert P. Li
A large number of drug candidates fail during clinical trials although they have been tested extensively in laboratory animals. Optimization of human drug properties with a human in vitro system will aid the selection of drug candidates with a higher probability of clinical success. Primary human hepatocytes that contain human-specific drug metabolism capacity represent an important human in vitro system for the evaluation of metabolic stability, metabolic fate, toxicity, and drug-drug interaction potential. The recent success in the cryopreservation of human hepatocytes has significantly enhanced the practical application of this valuable experimental system.

2:05 Decision-Making Properties of PK/ADME in Drug Discovery and Candidate Selection
Dr. Toru Horie, President, Dethree Research Laboratories
At the drug discovery stage, it is very important to provide information about critical aspects of PK/ADME of a candidate, including extent of absorption (transporter and insolubility), half-life, bioavailability, occurrence of active metabolite, major interspecies differences, inhibition and induction of CYPs (CYP1A1 or CYP3A4), and early in vitro studies in human tissues.

2:35 The Use of Computational Models to Predict ADME Parameters
Dr. Michael H. Tarbit, Managing Director, Camitro UK Ltd.
Pharmaceutical R&D is undergoing a revolution in drug discovery and development, with developments such as genomics, combinatorial chemistry, and high-throughput screening now driving a radically new process for discovery of novel drugs. A definition of a good medicine is a balance of potency, safety, and pharmacokinetics. It is therefore important that the concepts of pharmacokinetic and metabolic support and toxicity evaluation, which are essential elements in lead optimization, change in tandem with the developments in leads discovery. The history of DMPK and toxicology in the pharmaceutical industry has been one of traditional focus on generating data in support of regulatory filings, with little concern for understanding the underlying mechanisms that dictate a pharmacokinetic profile. This seems set to change in a future where prediction of pharmacokinetic outcome in man, or even designing of an appropriate pharmacokinetic profile within compound library synthesis, will carry a major premium in successful, cost-effective drug discovery. In keeping with other parts of the drug discovery process, lead optimization is thus heading for the age of informatics-driven predictive models to aid decision making and drug design. The availability of large data sets of ADME parameters, and applications of modern computational tools is driving a new generation of predictive technology. The development of Camitro's ADME models and the science behind them will be discussed.

3:45 Utilization of Microarray Technology for Identification of BCRP/MXR/ABCP as a Transporter of Topo I Inhibitors with Indolocarbazole Structure
Dr. Hidehito Kotani, Group Leader, Department of Biomedicine, Functional Genomics, Banyu Tsukuba Research Institute
Our topoisomerase inhibitors have potent antitumor activity and unique indolocarbazole structure. We have established resistant cell lines with reduced accumulation of compound, correlated with increased efflux. To identify the factors involved in this resistance mechanism, DNA microarray technology was utilized to measure gene expression level of these resistant cells. Of 30,000 genes we have analyzed, ABC transporter family gene, BCRP, showed highest increase in the expression. Also, overexpression of BCRP resulted in increased resistance to our compound. These data suggested the importance of BCRP gene in resistance mechanism to our topoisomerase inhibitors.

4:15 Evaluating Drugs and NCEs as Enzyme Inducers: Application of Cultured Hepatocytes and Branched DNA (bDNA) Technology
Dr. Andrew Parkinson, Chief Executive Officer, XenoTech LLC
Enzyme induction, especially cytochrome P450 (CYP) induction, is an important cause of drug-drug interactions. This presentation will focus on the use of primary cultures of rat and human hepatocytes to evaluate the ability of drugs and new chemical entities (NCEs) to cause CYP enzyme induction in vitro. This presentation will also describe the measurement of CYP mRNA levels by a relatively straightforward and highly sensitive assay based on branched DNA (bDNA) technology. Examples will be given where induction of CYP activity and CYP mRNA levels agree well and where they agree poorly.

4:45 Use of Predictive ADME in Combinatorial Library Profiling and Lead Optimization
Dr. Osman F. Güner, Director of Lead Identification and Optimization, Accelrys, Inc.
Dr. Robert D. Brown, Director of Combinatorial Chemistry Consortium, Accelrys, Inc.
High-throughput in silico ADME models can be used to select subsets of combinatorial libraries based on not only diversity or similarity, but also a combination of various ADME properties as well. The contribution of the ADME property-based constraints can be weighted against diversity assessment. We present how the drug-like properties of the selected subset of libraries can be improved without compromising the diversity and coverage of the library. The process is demonstrated with several examples. Finally, we provide an example of how this process is used in lead optimization while both potency and pharmacokinetic properties are simultaneously optimized to yield potent candidates with better anticipated ADME characteristics.

8:30 Chairperson's Comments
Dr. Harren Jhoti, Founder and Chief Scientific Officer, Astex Technology Ltd.

8:35 From Crystal Structures to Novel Leads: New Approaches in Knowledge-Based Drug Design
Prof. Gerhard Klebe, Institute of Pharmaceutical Chemistry, University of Marburg
The enormous body of solved crystal structures provides thousands of answers on how molecules do recognize each other. This information can be used to derive rules for how potential drug molecules might bind to a protein receptor. They are implemented into tools for docking and de-novo design. Proteins recognize their substrates and ligands in binding pockets. A comparative analysis of such pockets allows one to detect functional similarities among proteins independent from sequence and fold homology and helps to suggest novel ligand portions in de-novo design. A detailed analysis of the binding-site features is required to identify hot spots of binding. This information is then translated into a pharmacophore hypothesis to embark upon a hierarchical multistep virtual screening search in large compound libraries. Most important in this strategy is a reliable ranking of the suggested hits. For this purpose we developed a new scoring function based on atom-atom pair contact preferences.

9:05 Structure-Based Design and Synthesis of Peptides and Proteins toward Basis of Drug and Microarray Developments
Dr. Hisakazu Mihara, Associate Professor, Department of Bioengineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology
In order to develop drug candidates as well as microarray devices, consideration of peptide and protein structures is beneficial to generate high specificity and selectivity. We have developed peptides and proteins that mimic the protein amyloid formation such as the prion protein and bind viral RNA specifically using non-natural amino acids. Design, synthesis, and analysis based on their structures are discussed to address the basis of drug and/or microarray developments.

9:35 Lead-like Properties Designed into Diverse Chemotypes
Dr. Armen M. Boldi, Staff Scientist, Research and Development, ChemRx Advanced Technologies, Inc.
For over the past ten years, high-throughput organic synthesis has allowed the rapid generation of small-molecule libraries. Lead-like libraries are needed for discovery in the pharmaceutical industry. Molecules of lower molecular weights and lower calculated logP values facilitate optimization of potent active molecules. We are developing both solid-phase and solution-phase small-molecule libraries of diverse chemotypes utilizing robust and general synthetic methodology. Particular attention is being placed on designing pharmacological properties into library compounds thereby enhancing their utility in medicinal chemistry programs. Both the design principles and the processes used to generate these libraries will be described.

10:45 Organic Synthesis Design by Computer
Prof. Kimito Funatsu, Department of Knowledge-Based Information Engineering, Toyohashi University of Technology
Reaction knowledge from a reaction database and the derivation and application to synthesis design will be discussed. Several examples will be presented.

11:15 Structure-Based Lead Discovery
Dr. Harren Jhoti
Astex Technology is a structure-based drug discovery company pioneering the use of high-throughput X-ray crystallography (HTX™) for the rapid identification of novel drug candidates. HTX™ technology is part of an integrated drug discovery platform that includes cutting-edge technologies covering all aspects of structure-based research: protein production, crystallization, structure determination, bioinformatics, and computational and medicinal chemistry. HTX™ technology applies innovation and automation to all stages of the gene-to-structure process; many hundreds of crystal structures of key protein targets are solved in a rapid and efficient way. A key bottleneck in the use of protein crystal structures for lead generation and optimization is the time-consuming and laborious process of obtaining protein/ligand complexes. Astex has developed an enabling technology, AutoSolve™ software, that has transformed the process of obtaining protein/ligand structures by increasing the throughput by two orders of magnitude. Using this proprietary technology, X-ray crystallography can, for the first time, be used for structural screening of compounds. Astex's Pyramid™ approach to structural screening identifies small-molecule fragments compatible with the shape and chemical nature of the active site. These fragments are developed into highly tractable drug candidates and optimized for potency and selectivity against therapeutic targets. This presentation will discuss progress in Astex's lead discovery and optimization projects and describe current work in protein (and protein/ligand) structure determination.

1:00 Chairperson's Comments
Dr. Alexey V. Eliseev, State University of New York at Buffalo; and Director of Chemistry, Therascope AG

1:05 Organic Synthesis in Solution Phase and Solid Phase toward a Library of Natural and Unnatural Products
Prof. Takashi Takahashi, Department of Applied Chemistry, Tokyo Institute of Technology
A library synthesis of small molecules is very important not only for drug discovery but also for finding novel material. Solution-phase and solid-phase syntheses of phytoalexin elicitor active oligosaccharides, activated vitamin D3 derivatives, and peptide minetics of b-strand secondary structure will be presented.

1:35 Dynamic Combinatorial Chemistry
Dr. Alexey V. Eliseev
This lecture will present dynamic combinatorial chemistry (DCC), an approach to molecular diversity generation and screening that involves reorganization of pools of compounds existing in a dynamic equilibrium via their interactions with the target. Such reorganization results in the formation of amplified amounts of those components that form the strongest complexes with the target and thereby simplifies their isolation and identification. DCC offers a new approach to drug discovery that combines library synthesis and screening in a single step and allows the rapid exploration and customization of pharmaceutical diversity space for a given target. We will consider most recent examples of the use of DCC to discover novel ligands for proteins and nucleic acids.

2:05 The Solid-Supported Synthesis of Peptide Turn Mimetics and Their Use as a Tool in Early Drug Discovery
Mr. Sean R. Klopfenstein, Principal Researcher, Procter & Gamble Pharmaceuticals
The design and synthesis of novel peptide turn mimetic scaffolds are the subject of this presentation. Solid-supported methods utilizing multicomponent condensation reactions in the synthesis of peptide turn mimetics have been developed. Transformation of this technology into a high-throughput synthetic platform and its application to the process of lead generation for early drug discovery will be discussed.

2:35 Bridging Automation and Chemistry: A Decade of R & D
Dr. Hossain Saneii, President and CEO, Advanced SynTech, Advanced ChemTech
Over the last decade, we witnessed a rapid advance in the new field of chemical science, combinatorial chemistry. The pharmaceutical industries invested heavily in accelerating the development of this new technology. As a result, it is now involved in most of the processes in drug discovery and development. Chemists are facing increasingly high demand for novel compound libraries with drug-like properties to be screened against a rapidly growing range of targets in the post-genomic era. Integration of innovative chemistry technologies and the state-of-the-art automation is the key to accomplishing these challenges. We have re-engineered strategies for the syntheses of combinatorial libraries by developing new concept to create novel and biologically relevant scaffolds with the combination of state-of-the-art robotic instrumentation compatible to the challenging chemistry. This talk will outline our approaches to the rapid generation of heterocyclic scaffolds on solid support based on the "Prolific TemplateTM" concept, and the integration of the state-of-the-art robotic instrumentation into challenging solid phase combinatorial syntheses.

3:35 Chairperson's Comments
Dr. Tom Barnett, Director, Cell Biology and Project Manager, Nuclear Receptors, Karo Bio USA, Inc.

3:40 TRAP: A Chemogenomics Technology for High-Efficiency Drug Discovery
Dr. Graeme Martin, Chief Technical Officer, Telik, Inc.
Conventional drug lead discovery is resource intensive, requiring access to extensive chemical libraries and assays amenable to random high-throughput screening. To increase the efficiency of this process, Telik has developed a chemogenomics technology, Target Related Affinity Profiling (TRAP). Instead of using chemical attributes as the foundation for identifying candidate drug molecules, TRAP uses biological descriptors comprising affinity values for a proprietary panel of 15 to 20 proteins that collectively simulate most of the significant interactions between a small molecule and a potential drug target. Using TRAP, Telik has consistently identified active molecules for a diverse array of novel drug targets after screening only 200 compounds. TRAP therefore offers a high-efficiency, cost-effective approach to drug lead identification and rapid target validation, making it ideally suited to drug discovery in the post-genomic era.

4:10 Discovery and Development of Novel Nuclear Hormone Receptor Ligands
Dr. Tom Barnett
Nuclear hormone receptors are ligand-dependent transcription factors that are important targets for multiple metabolic and oncology indications. The androgen receptor is an important target for prostate cancer, androgenic alopecia, osteoporosis, and male hormone replacement therapy. A multidisciplinary approach that uses cell-based assay systems, Molecular Braille®, and structure-based drug design for the identification and optimization of novel tissue-specific ligands for the androgen receptor will be presented.

4:40 Single Live Cell Image-Based HTS Targeting Intracellular Enzymes: Caspases and Other Enzymes
Dr. Akira Komoriya, Chief Executive Officer, OncoImmunin, Inc.
A new class of highly cell-permeable fluorogenic protease substrates has been designed and synthesized using exciton theory rather than the conventional FRET approach. These new substrates exhibit significantly increased target enzyme specificity owing to the presence of unique folded structures and fuller enzyme-substrate amino acid sequence recognition. Substrates with these unique features have allowed the direct measurement of different groups of caspases in their physiological environments, i.e., in intact live cells. Generation of population data from single cell images has allowed precise characterization of temporal activation of various procaspases involved in apoptosis. The basic design used with the highly cell-permeable caspase substrates has been extended to the synthesis of substrates for other intracellular proteases such as Cathepsin D/beta secretase; it can be further extended to other classes of intracellular enzymes such as viral proteases and nucleases. Hence, one can carry out target identification, target validation, screening of large compound libraries, lead optimization, and ADME/Tox testing simultaneously in a multiwell-plate format.

Corporate Sponsor Biography

Astex Technology is a structure-based drug discovery company pioneering the use of high-throughput X-ray crystallography (HTX™) for the rapid identification of novel drug candidates. The company's unique structural screening approach couples in silico and X-ray crystallographic screening technologies; this is applied to detection and optimization of candidate drug compounds and small-molecule fragments against key proprietary and public-domain protein targets.

Corporate Sponsor Biography

Camitro Corporation, a wholly owned subsidiary of ArQule, Inc., is a pharmaceutical drug discovery technology company based in Menlo Park, California. The Company is a leading developer and provider of an integrated platform of predictive computational technologies and strategies for the in silico design, selection, and optimization of novel drug candidates with optimal ADME/Tox properties. The current technology release includes predictive models of human drug metabolism mediated by the cytochrome P450s 3A4, 2D6, and 2C9, blood-brain-barrier partitioning, and passive human intestinal absorption. Camitro's computational models relate compound structure directly to predicted ADME/Tox properties, thus enabling drug discovery scientists to evaluate and simultaneously optimize multiple ADME/Tox properties of drug candidates from the earliest stages of virtual library design through lead optimization.

Call for Exhibitors
This meeting will focus on the importance of informatics in the drug discovery process. This year, we expect at least 200 attendees to visit the exhibit hall. We strongly encourage any company with services or products related to target identification and validation, labchips, microarrays, SNPs, bioinformatics, library design, chemoinformatics, HTS, and ADME/Tox to consider sponsoring or exhibiting at this event. Please contact Mike Handy at 781-972-5492 for more information or to reserve a booth. Registrations received by December 7, 2001 will save your company up to $500!

Free Exhibit Hall Access
Up to 40 companies will be on display during the Drug Discovery Japan exhibition. This event has a proven record of providing networking opportunities with key industry leaders and now you can be there free of charge. Individuals interesting in interacting with this exclusive group should contact Edel O'Regan at eoregan@healthtech.com or 781-972-5423 or fax: 781-972-5425.

Please note: Passes are available at no charge until December 28, 2001. After this date or onsite a $25 fee will apply. Complimentary Exhibit Hall passes do not include access to the conference sessions.

Hotel Information
The Keio Plaza Inter-Continental Hotel
2-2-1, Nishi-Shinjuku
Shinjuku-ku, Tokyo, Japan 160-8330
T: 81-3-3344-0111 o F: 81-3-3345-8269
Room Rates: ¥16,000 single o ¥18,000 double
Cut-off Date: December 28, 2001
To Reserve a Room:
You must call the hotel's Los Angeles Office at 800-222-5346 or 213-362-7767 or fax 213-362-7772, attn: Ms. Mina Segal.
Please identify yourself as a Cambridge Healthtech Institute attendee to receive this special discounted rate.

Travel Information
Special Airline Discounts Available
Special discount fares have been established on United Airlines for this conference for flights originating in the US only. Please call Great International and National Travel at 617-527-0800 and ask for Joyce Dunn or e-mail her at jdunn@greatintltravel.com. Or you may call the United Airlines International Reservations Center directly at 800-521-4041. You must reference ID # 550WT.

Call for Posters
Cambridge Healthtech Institute encourages attendees to gain further exposure by presenting their work in the poster sessions. Please fill out the registration form, with the poster title and primary author. To ensure inclusion in the conference binder, a one-page summary must be submitted and registration must be paid in full by December 21, 2001. Click here for poster instructions

Corporate Sponsor:

Corporate Support:

Sponsoring Publications: Asia Pacific Biotech News Current Drug Discovery Drug Discovery & Development Genomics & Proteomics Innovation The Journal of Computer-Aided Molecular Design Online Journal of Bioinformatics

Cambridge Healthtech Institute proudly presents the Genomic Reports Series
	CHI’s Genomic Reports provide comprehensive coverage of business and technical issues in such key areas as target validation, bioinformatics, microarray informatics, and pharmacogenomics. Each report is based on more than 100 hours of primary research and contains 80 to 250 pages of peer-reviewed information in print and electronic formats. For details on reports visit www.chireports.com