|
REGISTER
5 Conferences
Exhibition
Additional Info
Get Involved
|
 |
|
|
|
Targets in Context - Linking Targets to Diseases Agenda
Drug Discovery & Development Week 2009: August 3-6, 2009· The World Trade Center Boston and Seaport Hotel · Boston, MA
|
 |
|
|
Pre-Conference Workshops - Tuesday, August 4, 2009
Pre-Conference Workshop I RNAi in Practice: A User's Guide to Assays and Screening in Mammalian Cells
Workshop Instructors:
Eberhard Krausz, Ph.D., Director, Discovery Assay Technologies (DAT), European Discovery Capabilities (EDC), Tibotec / J&J, Belgium
Steven Haney, Ph.D., Biological Profiling, Target Generation Unit, Pfizer Research Technology Center
Introduction:
The major tool for in vitro target identification and validation in mammalian cells is the application of RNA interference. The workshop intends to provide beginners as well as experts with a comprehensive overview on current practice in performing RNAi experiments. Various RNAi technologies will be introduced and compared. ‘Good practice' and the manifold challenges of designing and implementing assays and screens will be discussed. Finally, data evaluation and appropriate hit verification strategies will be delineated.
The workshop will be offered in an informal and interactive way to encourage lively discussion and free exchange of information, views and experience.
9:00
Opening Remarks & Introduction of Workshop Leaders
9:10
Development and Production of RNAi Libraries
- What type of design algorithms to consider?
- Strategies to avoid off-target effects
- Chemically synthesized siRNAs
- Chemical modification of siRNA to make it more specific
- Enzymatically produced siRNAs
- shRNAs and viral vectors - pros and cons
- Strategies to assess the different technologies
- How many molecules per target do we need in a library?
10:10
Networking Refreshment Break in Exhibit & Poster Hall
10:30
How to Design and Set up A RNAi Assay?
- What to consider when choosing an assay?
- The advantages of multi-parametric assays
- What are the tools in the box?
- Which RNAi technology is the most appropriate for my project?
- Which controls should be incorporated into RNAi experiments?
- Which delivery technologies are available?
- How to optimize transfection while avoiding off-target effects and cytotoxicicity?
- How to verify functionality of RNAi molecules?
- How to optimize an assay towards screening?
- Pros and cons of various screening strategies.
- The challenge of high variance in RNAi experiments, and what are true hits?
- Challenges given by ineffective molecules and off-target effects.
- How to delineate an appropriate hit verification strategy?
12:00
Roundtable Discussion and Q&A
Pre-Conference Workshop II Non-Invasive, Label-Free Assays - Getting the Most Out of your Targets and a Handle on Off-Target Effects
Workshop Introduction:
The xCELLigence RT-CA system provides time-dependent cell response profiles which can be used to assess the interaction of small molecule compounds and biologics with specific targets. Some of the key features of the xCELLigence system such as non-invasive and label-free measurements allow for assessment of targets in appropriate cell types and under physiologically relevant conditions. The real-time kinetic readout can provide information about both on target and off-target effects.
In this workshop we will discuss how the xCELLigence system can be used to assess the interaction of agonist with GPCRs and how the real-time profiles of the xCELLigence system can be used to discriminate between different modes of interaction. Also, we will present data demonstrating how to utilize the power of siRNA and shRNA knockdown of specific targets in conjunction with real-time monitoring of xCELLigence system for target identification and validation. Finally, we will show how time-dependent cell response profiles can be used to identify potential off-target effects of small molecule compounds.
Case studies presented by end-users of the xCELLigence RT-CA system will illustrate successful implementation of the system in target discovery, target validation, modulation and assessment of off-target effects.
The Workshop will commence at 1:30pm and end at 5:00pm, with a networking refreshment break of 30 minutes in between.
1:30
Introduction by Workshop Sponsor
1:40
The xCELLigence System: From Target Discovery, Validation and Modulation to Assessment of Off-Target Effects
The xCELLigence RT-CA system provides time-dependent cell response profiles which can be used to assess the interaction of small molecule compounds and biologics with specific targets. Some of the key features of the xCELLigence system such as non-invasive and label-free measurements allow for assessment of targets in appropriate cell types and under physiologically relevant conditions. The real-time kinetic readout can provide information about both on target and off-target effects. In this workshop we will discuss how the xCELLigence system can be used to assess the interaction of agonist with GPCRs and how the real-time profiles of the xCELLigence system can be used to discriminate between different modes of interaction. Also, we will present data demonstrating how to utilize the power of siRNA and shRNA knockdown of specific targets in conjunction with real-time monitoring of xCELLigence system for target identification and validation. Finally, we will show how time-dependent cell response profiles can be used to identify potential off-target effects of small molecule compounds.
Yama A. Abassi, Ph.D., Senior Director, Cell Biology and Assay Development, ACEA Biosciences
2:35
Monitoring the multiple signalling pathways of G protein-coupled receptors; Insights into the molecular determinants of ligand-biased signalling
Classically, GPCR ligands are classified as agonists, neutral antagonists or inverse agonists acting either orthosterically or allosterically to control signalling efficacy. According to receptor-occupancy theory, the efficacy is considered an intrinsic property of the ligand/receptor pair, and was often assumed to be the same for all the responses evoked. However, recent observations indicate that distinct signalling pathways engaged by a specific receptor can be differentially regulated by a given ligand that can sometimes have inverse efficacies on different signalling output (ligand-biased signalling). In molecular terms, these results suggest that ligands stabilize distinct receptor conformations that differentially regulate subsets of the signalling pathways engaged by the receptor. To better understand the molecular mechanisms directing ligand-biased signalling we developed new assays based on luminescence and resonance energy transfer that allow monitoring multiple signalling pathways and to assess the structural determinants of ligand-biased signalling. We will describe the development of novel Bioluminescence Resonance Energy Transfer (BRET)-based assays and the use of label-free methods based on impedance measurements that allow monitoring multiple signalling pathways and assessing the structural determinants of ligand-biased signalling.
Michel Bouvier, Ph.D., Department of Biochemistry, Institute for Research in Immunology and Cancer and Groupe de Recherche Universitaire sur le Medicament, Universite de Montreal, Canada
3:30
Networking Refreshment Break
4:00
Cell-based Assays for Analyzing Off-Target Effects of Antibacterials and Anti-retrovirals
Mitochondria have their own DNA (mtDNA) and ribosomes. Thirteen proteins are encoded by mtDNA and made on mitochondrial ribosomes. These proteins are involved in energy production. Antibacterials which target the bacterial ribosome as their primary mode of action can impair protein synthesis within the host's mitochondria since the bacterial ribosome and the host's mitochondrial ribosome share structural similarities. Hence, antibacterials can deplete mitochondrial DNA-encoded proteins. Anti-retrovirals which target HIV reverse transcriptase as their primary mode of action can impair the enzyme responsible for mitochondrial DNA replication as an off-target. This leads to depletion of mtDNA and, hence, to depletion of mtDNA-encoded proteins. Hence, both antibacterials and anti-retrovirals can decrease mtDNA-encoded protein levels which can lead to serious adverse events such as lactic acidosis, lipodystrophy, and myelosuppression. We have used the xCELLigence system to monitor the effects of antibacterials and anti-retrovirals on HepG2 cell growth over several days. This platform was a convenient way for monitoring the effects of these drugs in real-time in a non-invasive manner and also enabled us to monitor cell growth after compound removal unlike end-point assays. The xCELLigence system showed that some of the antibacterials and anti-retrovirals had a cytostatic effect on HepG2 cells. Further mechanistic studies were done using a high content screening assay that measures mtDNA-encoded protein levels in cells. Most of the antibacterials and anti-retrovirals which caused a cytostatic effect also caused a decrease in mtDNA-encoded protein levels.
Sashi Nadanaciva, D.Phil., Principal Scientist, Compound Safety Prediction, Pfizer Global R&D
Plenary Keynote
5:20
Keynote Introduction
Osamu Sato, Ph.D., Director & Head of Medical Writing Group, Daiichi-Sankyo Co., Ltd., Japan
5:25
Global Pharma Innovator: Daiichi Sankyo's Challenge to Build a Competitive Pharmaceutical Company in the Global Market
The current challenge for Japanese pharmaceutical companies to stay competitive in the global marketplace, is to expand product offerings and sales and increase R&D and clinical development capabilities in the U.S., Europe and other markets outside of Japan. This presentation will discuss Daiichi Sankyo's vision and strategy for transforming itself from a Japan-based pharmaceutical company to a truly global pharmaceutical player. Recent implementations of this strategy including the incorporation of Ranbaxy (India) and U3 Pharma (Germany) into the Daiichi Sankyo family will be discussed.
Takashi Shoda, President and CEO, Daiichi Sankyo Co., Ltd., Japan
6:00
Cocktail Reception in Exhibit & Poster Hall
Main Conference - Wednesday, August 5, 2009
7:30
Registration and Coffee
8:30
Conference Chair Opening Remarks
Ulrik Nielsen, Ph.D., Senior Vice President, Research, Merrimack Pharmaceuticals
Opening Address
8:40
Linking Targets to Disease: Lessons Learned and Future Directions
Anuk Das, Ph.D., Assistant Director, Immunology, Centocor
Genomics, Proteomics and Systems Biology Approaches to Finding the Right Target
9:05
Quantitative Proteomics/Metabolomics is a Tool for Investigating Drug Targets and Biological Phenomena
Proteomics and metabolomics based on mass spectrometry (MS) play important roles for biomarker discovery and target identification. Although MS is an unstable machine and sample preparation procedures are variable, reliable analytical methods are essential for understanding of mode-of-action of drug candidates. Technological progress and limitations will be discussed.
Yoshiya Oda, Ph.D., Director of omics Group, Laboratory of Core Technology, Eisai Co., Ltd., Japan
9:30
Using Biomarkers to Link Druggable Nodes to Clinically Relevant Pathways
A critical problem in drug discovery is the identification of druggable nodes that truly have the capacity to effect a disease state. We have developed a strategy for connecting the disease state to the drug development process using biomarkers as the tool for discovery of a drug candidate, and subsequent validation of the target molecule.
Stephen K. Horrigan, Ph.D., Vice President of Research, Avalon Pharmaceuticals
9:55
Human Genetics and Disease Relevant Targets: Linking Clinical Outcomes to Targets
Human genetics can be used to bring human disease relevant information about targets to the earliest part of the portfolio. Studying functional variants in the context of clinical outcomes provides insights into the human relevance of targets. Coupling this information with disease models and diverse therapeutic modalities will be discussed.
Albert B. Seymour, Ph.D., Director of Biological Profiling and Genetics, Biotherapeutics and Bioinnovation Center, Pfizer, Inc.
10:20
Networking Refreshment Break in Exhibit & Poster Hall
11:00
Applied Systems Biology for Drug Response Profiling
We developed a technology that allows a quantitative view of the dynamics of thousands of proteins in individual cells in disease and following treatment. The technology enables measuring and linking the dynamics of each protein to cell phenotypes and fates. I'll present a case study in which the technology is used to gain a deeper understanding of a drug's mode of action and reveal proteins that correlate with and affect a cell's response to the drug.
Ariel A. Cohen, Ph.D., Postdoc, Weizmann Institute of Science, Israel
11:25
Systems Biology of Receptor Kinase Signaling in Drosophila - A Reliable and Quick Reference for Translational Research
Systems biology of signaling networks relevant for diseases lead to identification of novel drug targets. Taking advantage of well-conserved signaling cascades between Drosophila and humans, we discuss RTK signaling network under insulin and EGF pathways. Comparative proteomic analyses of Drosophila and human phosphor-proteomes revealed many published pY sites and novel sites. Conserved sites connect disease related pathways with the potential for discovery of drug targets and biomarkers for various cancers and neurodegenerative diseases.
Srinivasan Krishnamoorthy, Ph.D., Principal Scientist, Biological Sciences, Physical Sciences Inc.
11:50
Confirmation of JNJ-38877605 as a selective c-Met kinase inhibitor using quantitative chemical proteomics.
Clinical experience has suggested that for many protein kinase inhibitors "off target" activities result in dose limiting toxicities that prevent efficient inhibition of the target. Quantitative chemical proteomics affirms JNJ-38877605 as an exquisitely selective and potent c-Met kinase inhibitor that facilitates combination therapy with other standard of care and anti cancer agents.
Tim Perera, Ph.D., Section Head, Ortho Biotech Oncology Research & Development, Johnson & Johnson
12:15
Networking Luncheon in Exhibit & Poster Hall
In Vivo and Computational Approaches
2:00
Understanding Disease Neurobiology to Generate Predictive Translational Models
For compounds targeting novel biochemical mechanisms, preclinical evaluation of efficacy and safety in translational models based on human disease biology is a key strategy for increasing probability of success in subsequent clinical proof-of-concept trials. For CNS diseases, selected case studies in neurodegenerative disorders, schizophrenia, and stress-related psychiatric disorders are used to highlight the opportunities and challenges of pursuing this neurobiology-focused approach.
John H. Kehne, Ph.D., Founder, Translational Neuropharmacology Consulting
2:25
An Attempt to Translate In Vitro Responses into the Clinic Using Computationally Predicted Preclinical Data from ErbB Targeted Therapies
Quantitative, data-driven computational modeling of signal transduction networks can be used to identify targets, to design better therapeutics and to help guide the selection of indications or biomarkers. Using the ErbB signaling network as an example we will discuss how this systems approach helped to identify ErbB3 as a critical node in the pathway and present simulations suggesting that an anti-ErbB3 monoclonal antibody can effectively inhibit signaling. We will present data on MM-121, the first ErbB3 antagonist to enter clinical development, , which consistent with simulations inhibits the pathway and prevents the outgrowth of tumors in xenografted mice. Finally, using other therapies as an example, we will discuss how these mechanistic insights into the system may be translated into a clinical setting.
Birgit Schoeberl, Ph.D., Senior Director, Research, Merrimack Pharmaceuticals
2:50
Computational Elucidation of Signaling Pathway Alterations in Disease States
Cells respond to their environment via signaling pathways, in which extracellular cues trigger a cascade of information flow, culminating in a phenotypic cellular response. The disregulation of signaling pathways can be found across the entire spectrum of human disease. We use high content flow cytometry to measure multiple signaling pathway molecules in extremely high throughput, resulting in datasets containing thousands of single cells. We then employ probabilistic modeling approaches to characterize the underlying signaling pathways. We will discuss signaling alterations characterized in temporal follicular lymphoma samples, found to be indicative of progression and predictive of prognositic outcome.
Karen Sachs, Ph.D., Post Doctoral Fellow, Leukemia and Lymphoma Society Fellow, Stanford University School of Medicine
Conference Keynote
(open to all attendees and exhibit hall visitors)
3:15
Build-Couple-Pair Strategy for Diversity-Oriented Synthesis Yields a Unique Compound Collection for Probe Development and Drug Discovery
This presentation will describe progress towards creating a screening collection at the Broad Institute using the build-couple-pair strategy for diversity-oriented synthesis. A case study of a DOS-derived small molecule that binds Hedgehog and blocks its signaling in human cells by disrupting a protein/protein interaction will be presented as an example of the utility of this screening collection against ‘undruggable' targets.
Michael Foley, Ph.D., Director, Chemical Biology Platform, Broad Institute at MIT and Harvard University
3:45
Networking Refreshment Break in Exhibit & Poster Hall
RNAi Approaches To Target Validation
4:30
Genome-Wide High-Content siRNA Screens Reveal Challenges and Limitations of Current siRNA Technology
Multi-parametric cell-based assays and RNA interference technology are used for functional genomics in academia and for target identification and validation in the pharmaceutical sector. The more complex the assay read-out, the more difficult it is to identify multiple RNAi molecules per target that share a common profile across the multiple parameters of the induced phenotype. Complex data analysis allows discrimination of on-target phenotype parameters from off-target effects. Impacts on the screening and hit verification strategies will be discussed. Also, highly multi-parametric analysis might serve as a very sensitive tool for improving current siRNA design and technology development.
Eberhard Krausz, Ph.D., Director, Discovery Assay Technologies (DAT), European Discovery Capabilities (EDC), Tibotec / J&J, Belgium
4:55
Focused siRNA Screens in Disease Based Assays: The Fast Track to a Target
Abstract not available at time of print.
Alex Gaither Ph.D., Laboratory Head, Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research
6:00
Attendee Networking Dinner in Boston
Join fellow attendees of Targets in Context - Linking Targets to Diseases conference for an evening networking dinner. Space is limited and an additional fee applies.
Main Conference - Thursday, August 6, 2009
8:40
Conference Chair Opening Remarks
Michael D. Winther, Ph.D., Senior Director, Drug Discovery, Xenon Pharmaceuticals, Inc.
High Content / High Throughput Screening & Assay Approaches
8:45
Ligands of Orphan GPCRs Identified from Inducible Expression of the Receptors and Cell-based Reporter Screen
It is often difficult to develop assays for orphan GPCRs that are constitutively active or cytotoxic when expressed at high levels. In this report, we show that a functional cell-based reporter screen can be developed using the constitutive activity of the receptor regulated under an inducible expression vector.
Paul Lee, Ph.D., Principal Scientist, Lead Discovery, Amgen Inc.
9:10
Comparison of Whole-Cell, Label-Free Assays for GPCR Drug Discovery
Label-free whole-cell assays are becoming an important supplement to traditional GPCR assays. These assays add the sensitivity to detect endogenously expressed receptors as well as the ability to qualitatively distinguish changes in G-protein coupling. These advantages are now well established for the cellular impedance (CellKey) assays. Newer platforms (Bind, Epic) use a different detection method, light-refraction, yet are reported to offer similar capabilities. Here, we directly compare these three platforms on GPCRs coupled to Gi, Gs, and Gq as well as a ligand-gated ion channel.
Matthew Peters, Ph.D., Senior Scientist, Lead Generation, Astra Zeneca
9:35
In Vivo Chemical Screening in Zebrafish
This presentation will discuss a few examples of chemical screens in zebrafish and their applications in therapeutic development.
Joanna Yeh, Ph.D., Instructor, Cardiovascular Research Center, Massachusetts General Hospital
10:00
Label-Free Detection of Chemotactic and Other GPCR Responses Using EPIC Technology
Chemotactic stimulation of non-adherent cells produces a robust signal in Resonant Waveguide Grating Optical biosensor (EPIC), and enhanced random cell movement as observed by time-lapse microsopy. Qualitatively different signals are generated on EPIC at low (chemotaxis-promoting) versus high (chemotaxis-suppressing) ligand concentrations, indicating complex signaling involved in the chmotactic response.
Marc Lamphier, Ph.D., Scientist, Eisai Research Institute
10:30
Networking Refreshment Break
11:00
Capturing the Complexity of Cellular Systems
We have engineered an integrated system comprised of hundreds of discrete high-content signal transduction assays, high throughput automated confocal microscopy, and the requisite IT infrastructure and analytical capabilities to mine the high volume of resultant data. This platform has been used to profile the activity of thousands of small molecule compounds, biologics, and RNAis at the sub-cellular level. These efforts have resulted in the identification of novel drug candidates, and shorter timelines for preclinical drug discovery. In addition, the massively parallel process and the richness of data provide a unique understanding of the geography and mechanics of the signal transduction process.
John Westwick, Ph.D., President & CEO, Odyssey Thera, Inc.
11:25
Tissue Engineered Tumor Niches as Drug Testing Platforms
Monolayer cell-based assays used within the pharmaceutical industry poorly represent the microenvironment of the tumor and thus have limited correlation to the clinical efficacy of a compound. Tissue engineered oncology assays can increase confidence in therapeutic efficacy, reduce the time and expense of animal studies, and potentially reduce pipeline attrition.
Eric YH Park, Ph.D., Senior Scientist, Pfizer Research Technology Center
Technology Workshop
11:50
Technology Presentation - Available for Sponsorship
IBC's technology workshops offer suppliers and service companies the opportunity to present their exciting technologies in drug discovery and development during the conference sessions. For more information on presenting a technology workshop at this meeting, please contact us.
12:15
Networking Luncheon with Attendee/Speaker Chat Sessions
These informal chat sessions will be led by conference speakers or industry leaders. Attendees can pick a topic, join a table and meet fellow attendees and speakers. Additional topics will be added. To suggest a discussion topic, Please contact us.
Discussion topics include:
- Getting The Most Out Of Your Images - Current Tools and Limitations, and Future Development
- New In-Vivo Models - Issues in Evolving and Adapting Well-Established Models
Discussion Leader: John H. Kehne, Ph.D., Founder, Translational Neuropharmacology Consulting
- Safety & Toxicity Assay Challenges and Advances
- Trends Towards In Vitro and In Silico Models
- Label-Free Assays - Applications and Limitations
Case Studies to Illustrate Preclinical To Clinical Translation - Ensuring the Ultimate Clinical Success Of Your Targets
2:00
Innovation by Novel and Established Drug Targets
Activities for the identification and validation of novel drug targets will be presented. Despite the innovation due to discovery of new targets, however, insight into the molecular mechanisms of previously established drug targets leads to new innovative approaches as well. Examples will be given.
Khusru Asadullah, M.D., Vice President & Head of Target Discovery, Bayer Schering Pharma AG
2:25
Novel Small Molecule Sirtuin 1 Activators for the Treatment of Metabolic Disease and Diseases of Aging
Sirtris has developed novel small molecule Sirtuin1 (SIRT1) activators. SIRT1 mediates many of the positive benefits of caloric restriction. Thus small molecule SIRT1 activators have the potential to treat many of the diseases of aging including Type 2 Diabetes (T2D) and neurodegenerative diseases. Positive data on SIRT1 activators in animal models and in clinical trials of T2D will be presented.
James L. Ellis, Ph.D., Vice President, Preclinical Research, Sirtris, a GSK company
2:50
Modifying Lipid Biosynthesis to Treat Diabesity
Recent studies have revealed the deep integration of molecular pathways involved in both diabetes and obesity, giving rise to the concept of ‘Diabesity' to describe these pathological conditions. Recent progress in developing inhibitors of Strearoyl CoA Desaturase, and advancing them through the drug discovery process, will be discussed to illustrate some of the issues faced in developing novel therapeutics to treat obesity and diabetes.
Michael D. Winther, Ph.D., Senior Director, Drug Discovery, Xenon Pharmaceuticals Inc.
3:15
Networking Refreshment Break
3:45
INK128 - A novel and highly selective mTORC1 and mTORC2 Kinase Inhibitor
Two mTORC1 selective inhibitors (rapamycin analogs) were approved for the treatment of renal cell cancer. Recent research has hypothesized that inhibition of both mTORC1 and mTORC2 may achieve even greater clinical efficacy than mTORC1 inhibitors. INK128 developed by Intellikine is a novel, potent and selective small molecule mTORC1/2 dual inhibitor.
Yi Liu, Ph.D., Vice President, Drug Discovery, R&D, Intellikine
4:10
AKT Inhibition and The Emerging Role of Perifosine in The Treatment of Multiple Myeloma
Abstract not available at time of print.
Paul Richardson, M.D., Clinical Director, Jerome Lipper Center for Multiple Myeloma, Department of Adult Oncology, Dana-Farber Cancer Institute
4:35
Dissecting the Molecular Mediators of Inflammation-Induced Urinary Bladder Overactivity
The clinical prevalence of urinary bladder overactivity is high with a poorly defined etiology. Prostglandin E2 is upregulated in both patients and preclinical overactivity models, and NSAIDS are widely efficacious. We investigated the molecular mediators of prostaglandin E2-induced bladder overactivity identifying key players, including GPCRs and ion channels.
Kevin Thorneloe, Ph.D., Investigator, Metabolic Pathways CEDD, GlaxoSmithKline Pharmaceuticals
|
|
|
|
