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Drug Discovery
Technology 2000
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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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