Download Brochure
Agenda
| Pre-Conference Workshops Wednesday, September 24, 2008 | DAY ONE | DAY TWO | DAY THREE | | |
| siRNA Screening For Drug Discovery | |
| Workshop Instructors: Silencing of gene expression by RNA inference (RNAi) has become a powerful tool for drug target discovery. It provides a simple, fast and cost-effective alternative to anti-sense and gene knockout techniques to create loss-of-function phenotypes and study gene functions. Large-scale RNAi screening has successfully identified potential therapeutic targets including STIM sensors and CRAC channels that are important for store-operated calcium entry. In mammalian cells small interfering RNAs (siRNAs) induce sequence-specific gene silencing by exploiting the endogenous RNAi pathway. Several types of siRNA libraries are available for high-throughput functional genomic screens for drug discovery. You Will Learn:
| |
| Label-free Cell Based Assays in Biomolecular Screening | |
| Workshop Instructor: In recent years, the incorporation of cell based assays in the early, high throughput phases of drug discovery has undergone a dramatic increase. This is largely driven by the fact that such assays yield data that more accurately model the complex biological states of receptor targets than biochemical assays. Additionally, these assays provide economy, convenience and throughput unattainable in in vivo studies. As part of this growing trend, label free cell based assays are being adopted at growing rates and offer many advantages to biomolecular screening including simplified assay development and access to more biorelevant data early in the drug discovery lifecycle. Here we will review a number of the currently available technologies and discuss their application, advantages and disadvantages to drug discovery efforts. You Will Learn:
| |
| Fluorescent Screening Tools for Drug Discovery | |
| Workshop Instructor: Over the past 10 years fluorescence has become a dominant detection technology in high throughput and cell-based (high content) drug discovery. While fluorescence is a very powerful detection technology many aspects are relatively complicated. The basis of the technology must be well understood to be used properly. Creation of new assay formats requires even more sophistication. This workshop aims to provide a good understanding of the technology, examples of its use and projections into future developments. You Will Learn:
| |
| Workshop Schedule | |
| 7:30 | Registration |
| 8:30 | Workshop Part I |
| 9:45 | Refreshment Break |
| 10:00 | Workshop Part II |
| 11:30 | Workshop Ends |
| Main Conference- DAY ONE Wednesday, September 24, 2008 | Pre-Conference Workshops | DAY TWO | DAY THREE | | |
| Conference Kick-Off - ACT 2008 Opening Keynotes Offering the Latest Assessment of the Industry Landscape | |
| Protein Kinase Targets | |
| 1:00 | Chairperson's Opening Remarks Jessie M. English, Ph.D., Senior Director, Oncology Site Lead, Merck External Basic Research |
| Keynote Presentation | |
| 1:15 | Kinase Research 2008: Do We Believe What We See Or Do We See What We Believe? The kinase family is one of the largest target families in the human genome. It's key function in intercellular signal transduction for all organisms makes it a very attractive target class for therapeutic interventions in diseases. Structures have not just informed drug design but also provided insights into targeting the inactive or active form of the kinase, for targeting the global constellation of residues at the ATP site or less conserved additional pockets or single residues, and into targeting noncatalytic domains. However, despite the successful delivery of numerous kinase inhibitors as (potential) drugs with the appropriate selectivity, potency, and pharmacokinetic properties, research in this area remains complex. This presentation will focus on "lessons learned" and potential future directions of this exciting field of Research. Peter Mueller, Ph.D., CSO & Executive Vice President, Drug Innovation & Realization, Vertex Pharmaceuticals, Inc. |
| Examining the Potential of Current and Future Kinase Drug Discovery Efforts | |
| 2:00 | Kinase Inhibitors in the Clinic Currently over 150 therapeutic compounds that inhibit protein kinases have entered human clinical trials and another 500 appear to be under development at the pre-clinical stage. However, these are primarily for cancer chemotherapy application and have been designed to target only about two dozen kinases that are usually tyrosine-specific. With about 515 known human proteins kinases targeting over 500,000 phospho-sites, there is high potential for off target effects of existing clinical candidates, but tremendous opportunity for treatment of over 400 other diseases. This talk discusses the limitations of current kinase inhibitors and strategies to uncover and develop more appropriate kinase drug targets for wider clinical applications. Steven Pelech, Ph.D., President and CSO, Kinexus Bioinformatics Corporation; Professor, Department of Medicine, University of British Columbia |
| 2:30 | JAK2 Inhibitor - Update on Scientific Advancements JAK2 is an intracellular protein tyrosine kinase whose dysregulation has been implicated in leukemia, lymphoma, and myeloproliferative disorders (MPD). Increased kinase activity of JAK2, caused by point mutation of the JH2 autoinhibitory region or formation of JAK2 fusion proteins, causes increased activation of downstream signaling pathways affecting cell differentiation, proliferation, migration, and apoptosis. Mike V. McCuller, Ph.D., MBA, Vice President, Drug Discovery Operations, SuperGen, Inc. |
| 3:00 | Complex Effects of Kinase Activation State and Resistance Mutations on ABL Inhibitor Binding We have measured binding constants for "type I" and "type II" inhibitors across a panel of phosphorylated and unphosphorylated wild-type and imatinib-resistant ABL variants. Most resistance mutations selectively reduce type II affinity for the unphosphorylated state but do not affect phosphorylated state binding. These data provide direct biochemical evidence supporting the hypothesis that unphosphorylated ABL is the relevant imatinib target in vivo. They further show that nilotinib has a profile unique among the type II compounds and defines a novel inhibitor class. Patrick P. Zarrinkar, Ph.D.,Vice President, Technology Development, Ambit Biosciences |
| 3:30 | Networking Refreshment Break |
| Scientific Advisory Board Panel Discussion | |
| 4:00 | Future of Kinase Inhibitors in Drug Discovery
|
| Assay & Screening Advances | |
| 1:00 | Chairperson's Opening Remarks Wilson Blaine Knight, Ph.D., Vice President of Drug Discovery, Southern Research Institute |
| Keynote Presentation | |
| 1:15 | Ushering in the New Era of Opportunistic Gene and Drug Discovery Over the past decade advances in cell based assay technology, miniaturization, and automation have led to an opportunity to functionally molecules broadly against biological space in an unprecedented way. Libraries of compounds, genes, natural products, proteins, peptides, and novel polymeric substances can be profiled for new biological properties and attributes at a fraction of the time and cost, providing the life sciences, synthetic and materials sciences new directions for research and development. Advances in cell-based technologies from primary cell expansion, stem cell culture and alternative energy production hold promise as future applications for opportunistic discovery. Jeremy S. Caldwell, Ph.D., Executive Director, Molecular and Cell Biology, Genomics Institute of the Novartis Research Foundation |
| Assays and Screening Industry & Academia Strategies | |
| 2:00 | Enabling Routine Primary HCS on Large-Scale Libraries Primary high content (image-based) screens at Burnham's NIH Molecular Libraries Screening Center Network include: agonists and antagonists of VCAM-1 in HUVECs (VCAM-1 is essential for lymphocyte adherence), inhibitors of phagocytosis in mouse J774 macrophages, agonists of cardiomyocyte cell cycle entry of neonatal rat cardiac myocytes, compounds that alter β-catenin distribution in HeLa cells, alteration of lipogenesis in murine hepatocytes (AML-12), and upregulatation of p27 in HeLa cells. The progress on implementing and carrying out these screens with the NIH library of 200,000 compounds, which will grow to 500,000 in 2009, will be presented. Jeffrey Price, Ph.D., Associate Professor, The Burnham Institute for Medical Research |
| 2:30 | NIH Molecular Libraries Initiative: A New Academic Frontier in HTS and Chemical Biology Technology now exists to enable the development of chemical probes for every target for which a suitable high-throughput screening assay can be devised, thus reversing the normal sequence of events in early drug discovery. The NIH Molecular Libraries Initiative, begun in 2003, represented an ambitious multifaceted attempt to enable public sector researchers to use small molecules in their research, whether as tools to perturb genes and pathways, or as starting points for the development of new therapeutics for human disease. This presentation will discuss these developments, illustrated by projects from the NCGC. James Inglese, Ph.D., Deputy Director, NIH Chemical Genomics Center |
| 3:00 | Cellular Screening Strategies: Lessons from Phenotypic & Pathway Assays Lilly is using cell based phenotypic and pathway assays to chemically interrogate complex biological systems. Potential advantages of these approaches include direct identification of cell active compounds, inclusion of both known and unknown molecular components/mechanisms and interrogation of molecular targets in a relevant context. Cellular imaging is a robust technology to measure multiple aspects of cell cycle in non synchronized cells. Phenotypic profiles and compound activity fingerprints can be combined to identify compounds affecting cell cycle by both known and novel mechanisms. Jonathan Lee, Ph.D., Senior Research Advisor, Lead Generation and Optimization Biology, Eli Lilly and Company |
| 3:30 | Networking Refreshment Break |
| Scientific Advisory Board Panel Discussion | |
| 4:00 | Target Centric vs. Systems Biology: Relative Value Development, Tools and Technologies
|
| G-Protein Coupled Receptors | |
| 1:00 | Chairperson's Opening Remarks Terry Hébert, Ph.D., Associate Professor, Department of Pharmacology and Therapeutics, McGill University, Canada |
| Keynote Presentation | |
| 1:15 | G-Protein Coupled Receptors in 2008: Rethinking What We Thought We Knew Evolving knowledge regarding GPCR's has forced a rethinking of several concepts that underlie their role in physiological regulation and as drug targets. Such rethinking includes the need to address issues subsumed by questions that are simple to ask but that have recently proved more difficult to answer (or that have new "answers"):
|
| Revisiting G-Protein Coupled Receptors Pharmacology | |
| 2:00 | Connecting Allosteric Modulation with Pathway Selectivity Allosteric modulation of pathway selectivity at G protein coupled receptors depends on the existence of different conformations of the receptor that preferentially engage different coupling proteins (e.g., G proteins and kinases). The nature and abundance of these receptor conformations and the origin of allosteric modulation ultimately determine the feasibility of pathway selectivity and its potential exploitation in drug discovery. Fred Ehlert, Ph.D., Professor, Pharmacology, University of California School of Medicine, Irvine |
| 2:30 | Analyzing RGS Proteins that Modulate Kir3/GIRK Channel Activity in the Brain and Heart Regulators of G protein Signaling (RGS proteins) represent a large family of GTPase-activating proteins (>25) that accelerate the termination of GPCR signaling. These ubiquitous regulatory proteins modulate GPCR signaling in plants to animals, demonstrate cell-specific expression patterns in humans, and modulate the kinetics and magnitude of numerous neurotransmitter and hormone signals Studies in my lab are aimed at determining the selective or non-selective contribution of specific RGS proteins in GPCR regulation of neuronal and cardiac ion channels. Craig Doupnik, Ph.D., Associate Professor, Department of Molecular Pharmacology & Physiology, University of South Florida College of Medicine |
| 3:00 | Assessing G-protein Independent, b-Arrestin-Dependent Signaling Recently, several GPCRs, including protease-activated-receptor-2 (PAR-2), angiotensin-II Type IA receptor (AT1A), b2-adrenergic receptor (b2AR) and the parathyroid hormone receptor (PTHR) have been demonstrated to elicit signals through interaction with the scaffolding proteins, b-arrestins-1 and 2, independent of heterotrimeric G-protein coupling. This talk will focus on the distinct Gaq and b-arrestin-dependent signaling pathways of PAR-2, a receptor reported to have both protective and pro-inflammatory effects in allergic asthma and inflammatory bowel diseases and pro-metastatic effects in a number of tumor cells. Kathryn DeFea, Ph.D., Assistant Professor of Biomedical Sciences, University of California, Riverside |
| 3:30 | Networking Refreshment Break |
| Scientific Advisory Board Panel Discussion | |
| 4:00 | Implications of Changing Paradigms in GPCR Signaling on Drug Discovery
|
| Ion Channel Targets | |
| 1:00 | Chairperson's Opening Remarks Jesus "Tito" Gonzalez, Ph.D., Sr. Director, Biology, Vertex Pharmaceuticals Inc. |
| Keynote Presentation | |
| 1:15 | The Challenges of Ion Channel Drug Discovery –Case Histories Ion channels are important targets for identifying novel therapeutic agents to treat a wide variety of diseases. Traditionally, development of new drugs directed against this target class has been difficult. A significant challenge associated with molecular-based ion channel drug discovery and development is the identification of potent and selective small molecule leads for medicinal chemistry optimization. Recently, a number of unique, functional high throughput screening strategies were devised that have been successful in identifying chemically tractable leads from large compound libraries. Several case histories focusing on the design and implementation of these new approaches to ion channel drug discovery will be presented. Greg Kaczorowski, Ph.D., Senior Director, Ion Channel Department, Merck Research Laboratories |
| CRAC Channels: Recent Advances in Biology and Drug Discovery | |
| 2:00 | Molecular Determinants of Store-operated Ca2+ Channel Activation Stim is a dual-function molecule that serves as an ER Ca2+ sensor and as a messenger that relays information to the plasma membrane to activate Ca2+ influx. Orai serves as the Ca2+-selective pore-forming subunit. I will present three levels of molecular coordination that lead to store-operated Ca2+ influx: depletion of the ER, migration of Stim to the plasma membrane; Stim interaction with Orai; and Stim and Orai migration to the immunological synapse. Michael Cahalan, Ph.D., Professor of Physiology & Biophysics, University of California, Irvine |
| 2:30 | Discovering Small Molecule CRAC Channel Inhibitors CalciMedica's drug discovery strategy targets CRAC channels. CRAC channels are key components of the Ca2+ signaling pathway in immune cells, which is essential for adaptive immune responses. CalciMedica has acquired exclusive rights to the molecular components of CRAC channels (Orai1-3 and STIM1-2) and is using these molecules to screen for novel small molecule inhibitors for the treatment of autoimmune diseases. Ken Stauderman, Ph.D., Vice President, Research, CalciMedica |
| 3:00 | Analyzing the Composition of SOCE Channels Involving TRPC1, STIM1, and Orai1 Studies reported by us and others have shown that TRPC1 is a component of store-operated calcium channels (SOCs), that are distinct from CRAC channels, and contributes to several cellular functions including salivary gland fluid secretion. Recent findings suggest that TRPC1-SOC requires functional interaction with CRAC channel components Orai1 and STIM1. Possible mechanism(s) involved in assembly and regulation of TRPC1-SOCs will be discussed. Indu S. Ambudkar, Ph.D., Chief, Molecular Physiology and Therapeutics Branch, NIDCR, NIH |
| 3:30 | Networking Refreshment Break |
| Scientific Advisory Board Panel Discussion | |
| 4:00 | Opportunities and Challenges of Ion Channel Drug Discovery
|
| 5:00-6:30 | Grand Opening of ACT 2008 UNIFIED Exhibit Hall and Networking Cocktail Reception with Poster Viewing Exhibit Hall Grand Opening Remarks: Donald P. Taylor. M.S., MBA, Senior Director, Marketing & Corporate Development, Cellumen, Inc. Sponsored by  |
| Main Conference- DAY TWO Thursday, September 25, 2008 | Pre-Conference Workshops | DAY ONE | DAY THREE | | |
| Protein Kinase Targets | |
| Assay & Screening Advances | |
| 8:30 | Chairperson's Opening Remarks |
| Keynote Presentation | |
| 8:45 | Latest Advances Surrounding Assays and Screening for Kinase Discovery Over the past 15 years, the potential of Protein Kinases (PKs) as therapeutic targets has been demonstrated. There are currently a multitude of protein kinase assay formats used in the discovery of modulators of the activity of this important class of enzymes. They range from binding and kinase catalytic activity assays, to cellular activities. The latter includes assays detecting direct phosphorylation events by target kinases to those designed to explore the modulation of cellular signaling pathways at multiple points. The selection of assay formats is dependent upon the question(s) one is trying to answer. In addition, kinases are regulated both by posttranslational modifications, the most pervasive being phosphorylation, as well as protein:protein interactions between the regulatory domains of the kinase and cellular proteins. Therefore, the selection of the form of the enzyme is also critical to the question(s) under exploration. The current status and future direction of kinase assay technologies and their uses will be discussed. Wilson Blaine Knight, Ph.D.,Vice President of Drug Discovery, Southern Research Institute |
| 9:30 | Selectivity and Specificity Analysis and Design in Scaffold-based Drug Discovery One of the many challenges in the design of kinase inhibitor lies in achieving the desired selectivity profile. Plexxikon's approach, beginning with weakly active, structurally characterized compounds, has repeatedly yielded lead compounds with excellent selectivity after a focused optimization process. Although the Scaffolds utilized to date have been uniformly ATP-site binding compounds, the resulting lead compounds have achieved potency and selectivity primarily though accessing binding determinants outside the ATP-site. In many cases, through the use of an iterative structure-guided approach, compounds have been designed to take advantage of kinase-specific conformational states, thus achieving dramatic selectivity between kinases with nearly identical sequences. Some examples of the platform and the approach will be discussed. D. R. Artis, Ph.D., Vice President, Lead Generation, Plexxikon, Inc. |
| 10:00 | Refreshment Break in Exhibit Hall with Poster Viewing |
| 10:30 | High Throughput Mass Spectrometry for Label-Free Enzyme and Cell Assays In this presentation, we highlight several therapeutic programs in which a combination of label-free mass spectrometry-based screening approaches have been leveraged to identify small molecule inhibitors to intractable targets. In the first example, RapidFireTM mass spectrometry was developed as a common platform to profile prolyl hydroxylase domain-containing enzyme (PHD) inhibitors across representative members of the Fe(II)/alpha-ketoglutarate-dependent super family of dioxygenases. This super family of enzymes catalyze the hydroxylation of diverse classes of substrate molecules and are generally intractable by conventional assay methods. In the second example, RapidFire™ MS is used with high resolution LTQ-Orbitrap® MS to identify inhibitors to ATP Citrate Lyase (ACL) and determine their effect in cells. These studies emphasizes the utility of RapidFireTM MS for compound profiling across diverse enzyme collections and demonstrates the broader utility of label-free MS approaches when used as a contiguous enzyme-to-cellular assay platform. Kurt Morgenstern, Ph.D., Principle Scientist, Lead Discovery, Amgen Inc. |
| 11:00 | Analysis of Cellular Signaling using Activation State-Specific Antibodies in Cell-based Assays Activation state-specific antibodies (eg. phospho-specific) are often used to examine aberrant cellular signaling associated with cancer and other diseases. These antibodies allow quantification of protein phosphorylation and other post-translational modifications like acetylation, methylation, and ubiquitinization. Signaling antibodies may be used in single endpoint HTS/HCS cell-based assays to screen large compound libraries or arranged in larger arrays to examine signaling in many different pathways or to monitor complex biological processes such as proliferation, apoptosis, stress, DNA damage, metabolism, inflammation, and cytotoxicity. These powerful antibody arrays can also be used to identify druggable targets or mutation-specific biomarkers, evaluate the efficacy of therapeutics in a cellular environment, or examine on- and off-target effects of compounds. Randall K. Wetzel, Ph.D., Clinical Applications/Cytometry, Cell Signaling Technology |
| 11:30 | Technology Workshop There are a limited number of technology workshop slots available. Please contact Jennifer McElligott at jmcelligott@ibcusa.com or 508-614-1672 for additional information. |
| 12:00 | Networking Luncheon in Exhibit Hall with Poster Viewing |
| G-Protein Coupled Receptors | |
| 8:30 | Chairperson's Opening Remarks |
| Impact of Oligomers | |
| Keynote Presentation | |
| 8:45 | Oligomers of the M2 Muscarinic Cholinergic Receptor and their Functional Consequences Much evidence suggests that GPCRs can exist as oligomers. Much else remains unclear, however, including such details as their size, their composition, and their prevalence and role in nature. GPCRs also can host cooperative effects, with implications for pharmacological selectivity and the mechanism of signaling. These issues will be reviewed in the context of our own approach, which utilizes mechanistic models to account for the interactions among receptors, G proteins, and their respective ligands. Such models have been applied to data from preparations in which the receptors are monomeric or oligomeric, with the M2 receptor taken as the case in point. Predictions regarding properties such as oligomeric size have been compared with the results from biochemical and biophysical studies. James W. Wells, Ph.D., Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Canada |
| 9:30 | Asymmetry and Ligand Sensitivity in Dimeric Associations of the Serotonin 5HT2c Receptor GPCR's respond to external stimuli by activating heterotrimeric G proteins inside the cell. There is increasing evidence that many GPCRs exist as dimers or higher oligomers, but the biochemical nature of such dimers and what roles they have, if any, in signal transduction remains unclear. We conducted a comprehensive study of dimerization of the 5HT2c serotonin receptor using disulphide-trapping experiments. We introduced cysteine mutants at positions we thought could be accessible and sufficiently close to the extra-cellular surface to allow oxidation, based on a model of 5HT2c on the structure of Rhodopsin. We found a dimer interface between transmembran™ helices IV and V that is markedly sensitive to the state of receptor activation. This presentation will discuss our discoveries. Filippo Mancia, Ph.D., Professor, Columbia University |
| 10:00 | Refreshment Break in Exhibit Hall with Poster Viewing |
| 10:30 | Self-Assembled Lipid Bilayers for the Investigation ofGPCR Oligomeric States We dissected the functional role of individual monomers and dimers of G-Protein Coupled Receptors (GPCRs) by utilizing engineered high density lipoproteins (Nanodiscs) to confine a defined number of protomers within a soluble native-like phospholipid bilayer of defined size. We document the signaling activity of monomeric beta2AR and rhodopsin and show that the dimeric rhodopsin couples to only a single transducin. Stephen G. Sliger, Ph.D., Director, School of Molecular & Cellular Biology, University of Illinois, Urbana |
| 11:00 | Assembly of Specific GPCR Signaling Complexes Distinct stable receptor-based signalling complexes are formed during receptor biosynthesis and contain G proteins, effectors and possibly other regulatory molecules as well. These complexes may remain associated during cellular signalling but other molecules may also be specifically recruited to participate in a diversity of signalling events. Our work is aimed at characterizing individual GPCR signalling complexes, their organization, trafficking and sites of assembly. Terry Hébert, Ph.D., Associate Professor, Department of Pharmacology and Therapeutics, McGill University, Canada |
| 11:30 | Technology Workshop There are a limited number of technology workshop slots available. Please contact Jennifer McElligott at jmcelligott@ibcusa.com or 508-614-1672 for additional information. |
| 12:00 | Networking Luncheon in Exhibit Hall with Poster Viewing |
| Ion Channel Targets | |
| 8:45 | Chairperson's Opening Remarks |
| Assessing TRP Channel Advancements | |
| 9:00 | Role of TRPA1 as a Polymodal Sensor of Noxious Stimuli Abstract to come. Ardem Patapoutian, Ph.D., Associate Professor, The Scripps Research Institute |
| 9:30 | In Search of Novel TRPA1 Antagonists TRPA1 is expressed in all types of pain transmitting neurons. Various animal and human studies have shown that activation of TRPA1 receptor induces severe pain, neuropeptide release and neurogenic inflammation. Thus targeting TRPA1 receptor provides a rationale for developing novel analgesic or anti-inflammatory agents. Research data from in vitro and in vivo studies on pain models will be presented. Neelima Khairatkar Joshi, Ph.D., Vice President, Biological Research, Glenmark Research Centre |
| 10:00 | Refreshment Break in Exhibit Hall with Poster Viewing |
| 10:30 | Irritant Induced Chronic Cough: Irritant Induced TRPpathy (TRPV1) Repeated inhalations of airborne irritants may cause airway inflammation, bronchospasm, lung function changes, airway hyperresponsiveness, or irritant-induced asthma. Further, chronic cough, from repeated irritant exposures, can be associated with release of inflammatory mediators, tachykinins and neurotrophins. Mechanistically, damage to the tracheobronchial tract could lead to enhanced TRPV1 (or TRPA) ion channel activation and an outcome considered to be a TRPV1pathy. Stuart Brooks, Ph.D., Professor, University of Southern Florida College of Public Health |
| 11:00 | AlphaScreen-based Protein Interaction Assays for TRPV4 Most TRP channels are subject to regulation by protein interactions that may represent important drug targets. Particularly, calmodulin binding has been demonstrated for many TRP channels. We have used a high-throughput proximity assay to identify CaM-dependent intramolecular interactions in TRPV4 as a new channel regulation mechanism. This technique provides a novel and sensitive method for the characterization of protein interactions. Rainer Strotmann, Ph.D., Research Assistant, Biochemistry, University of Leipzig, Germany |
| 11:30 | Technology Workshop There are a limited number of technology workshop slots available. Please contact Jennifer McElligott at jmcelligott@ibcusa.com or 508-614-1672 for additional information. |
| 12:00 | Networking Luncheon in Exhibit Hall with Poster Viewing |
| Protein Kinase Targets | |
| 1:45 | Chairperson's Remarks |
| The Latest Toxicological Issues | |
| 2:00 | Kinases of Toxicological Concern: Development of In Vitro - In Vivo Correlations for Kinase Inhibition & Toxicity Novel molecular and cell biologic approaches for detecting desirable and undesirable consequences of kinase inhibition will be explored with specific examples relating to bone marrow, cardiotoxicity, and clastogenicity. Through the use of kinase inhibition screening and retrospective analysis of in vivo toxicity data across the entire portfolio, several informative conclusions regarding kinases and their toxicological effects have been learned. The strategies and data discussed will provide practical approaches to early Discovery intervention/screening as it relates to in vitro methods of assessment of kinase inhibitor toxicology. Kyle L. Kolaja, Ph.D., D.A.B.T., Director, Discovery and Investigative Safety, Roche Pharmaceuticals |
| 2:30 | Toxicity of a Selective Lck Inhibitor is Apparently Target-Related An Lck inhibitor that blocked T cell activation was toxic at all dose groups in the rat. Further understanding of structure-activity relationships revealed a critical moiety for Lck inhibition. An analog was synthesized that lacked this critical moiety and both compounds were administered in a toxicity study. Similar findings were seen with the Lck inhibitor as in the previous study while the analog was not toxic at similar exposure. It was concluded that inhibition of Lck as a therapeutic modality appears to be limited by mechanism-based toxicity. Rob Stachlewitz, Ph.D., D.A.B.T., Principal Scientist, Toxicology and Safety Assessment, Boehringer Ingelheim Pharmaceuticals, Inc. |
| 3:00 | Technology Workshop There are a limited number of technology workshop slots available. Please contact J ennifer McElligott at jmcelligott@ibcusa.com or 508-614-1672 for additional information. |
| 3:30 | Refreshment Break in Exhibit Hall with Poster Viewing |
| Assay & Screening Advances | |
| G-Protein Coupled Receptors | |
| 1:45 | Chairperson's Remarks |
| 2:00 | Preparation of Functional Human Cannabinoid Receptor CB2 for Structural Studies Structural studies on CB2 by NMR spectroscopy and other biophysical techniques will contribute greatly to the development of novel specific therapeutics targeting this receptor. Procedures suitable for production of mg-quantities of labeled CB2 are being developed. The ability of CB2-containing proteoliposomes to activate G-proteins in response to agonist binding was studied as a function of detergent, lipid, and CB2 concentration. On the order 50% of the lipid-reconstituted, purified CB2 is functional as determined by the G protein-coupled assay. Alexei Yeliseev, Ph.D., Staff Scientist, LMBB, NIH NIAAA |
| 2:30 | Development of a Homogeneous TR-FRET Assay to Determine GPCR Ubiquitinylation upon Agonist Activation G-protein coupled receptor (GPCR) ubiquitinylation is important to understand receptor biology and to predict receptor localization after agonist activation. Immunoprecipitation is the most common approach for this study, but it is laborious and time consuming. We will report a robust and homogenous cell-based assay to detect GPCR ubiquitinylation. Han Xu. Ph.D., Senior Scientist, Amgen Inc. |
| Technology Workshop | |
| 3:00 |   The xCELLigence system is a revolutionary impedance based technology which enables dynamic real-time, label-free cell-based analysis. Learn how long-term dynamic real-time data facilitates discovery not possible with end-point analysis, focuses assay development, and can improve compound attrition rates. Application data will be presented around functional monitoring of receptor Tyrosine Kinase and GPCR signaling. Yama Aref Abassi, Ph.D. Senior Director, Cell Biology & Assay Development, ACEA Biosciences Inc. |
| 3:30 | Refreshment Break in Exhibit Hall with Poster Viewing |
| Ion Channel Targets | |
| 1:45 | Chairperson's Remarks |
| Featured Presentation | |
| 2:00 | CFTR Modulators for Treating Cystic Fibrosis Cystic Fibrosis Transmembrane Regulator (CFTR) is member of the ABC transporter family that functions as a chloride channel and is important for ion transport across the epithelia of multiple organs. A variety of CFTR mutations affecting channel gating and trafficking cause Cystic Fibrosis (CF). A therapeutic approach for CF is identifying small molecules modulators that restore CFTR mutant activity. Here we describe progress toward this goal and the in vitro activity of CFTR potentiators and correctors. Additional Vertex contributors to this presentation were Peter Grootenhuis and Sabine Hadida Fred. Fred Van Goor, Ph.D., Research Fellow II, Vertex Pharmaceuticals, Inc |
| Kv1.3 Channel in Disease Applications | |
| 2:30 | Kv1.3 Channel Involvement in Multiple Sclerosis Abstract to come. George Chandy, Ph.D., Professor, University of California, Irvine |
| 3:00 | Technology Workshop There are a limited number of technology workshop slots available. Please contact Jennifer McElligott at jmcelligott@ibcusa.com or 508-614-1672 for additional information. |
| 3:30 | Refreshment Break in Exhibit Hall with Poster Viewing |
| 4:00 | Novel Recombinant Peptide Toxin Fusion Proteins as Potential Therapeutics for the Treatment of Autoimmune Disease Peptide toxins have evolved unique abilities to potently block ion channels. Sea anemone toxin ShK and scorpion peptide toxin OSK1 block voltage-gated potassium channel, Kv1.3. We describe the engineering of novel peptide toxins to block Kv1.3 as autoimmune disease treatments. Hung Nguyen, PhD. Principal Scientist, Protein Sciences, Amgen Inc. |
| 4:30 | Kv1.3 Channel Regulates Sensory Discrimination and Axon Targeting in the Olfactory System We show that mice with Kv1.3 gene-targeted deletion have an increased longeivity, a resistance to diet- and genetically-induced obesity via increased locomotion and metabolism, have increased odor discrimination and reduced threshold for detection, and in odor receptor tagged, genetically-engineered mice we can track changes in axon circuitry to the olfactory bulb. Intranasal insulin delivery to wild-type mice phosphorylates the channel to partially mimic the observed "super-smeller" phenotype of the knock-out. Debra Ann Fadool, Ph.D., Associate Professor, Biological Sciences, Florida State University |
| Protein Kinase Targets | |
| Assay & Screening Advances | |
| G-Protein Coupled Receptors | |
| NIH Molecular Libraries Probe Production Center Network (MLPCN) | |
| 4:00 | Overview - NIH Molecular Libraries Probe Production Center Network Gary A. Piazza, Ph.D., Manager, Associate Prof. of Pharmacology, Southern Research Institute, The University of Alabama at Birmingham |
| 4:05 | Principal Investigators from NIH Molecular Libraries Probe Production Center Network The NIH Molecular Libraries Screening Center Network (MLSCN) has undergoing several strategic changes during 2008. The new Molecular Libraries Probe Production Centers Network (MLPCN) will be composed of different types of centers to provide improved handling of assays and enhanced synthetic chemistry support for probe identification and development. Three types of centers have been identified to meet these challenges: Comprehensive Centers with the capability to screen 300-500K compounds against at least 25 assays per year, provide structure-activity relationship (SAR) analysis, and support chemistry to identify potent and selective chemical probes; Specialized Screening Centers with the capability to provide expertise and experience in specific technologies needed to successfully implement complex and technically difficult assays that may not be amenable to HTS (e.g., high content screening, phenotypic assays, ion channel screening, whole organism screening); and Specialized Chemistry Centers with outstanding capabilities in applying medicinal and synthetic chemistry in order to advance early hits to chemical probe status. As an integral part of the network, the Specialized Chemistry Centers will actively interact with both types of screening centers to generate probes. The integration of the probe pipeline, center cores and the overlapping roles of the comprehensive and specialized screening centers are envisioned to develop innovative chemical probes that will be used by the scientific community to study complex biological processes involved in human health and disease. Carson Loomis, Ph.D., NIH Molecular Libraries & Imaging Roadmap, Division of Extramural Research, National Human Genome Research Institute |
| 4:45 | MLPCN Question & Answer |
| 5:00 | Networking Cocktail Reception in Exhibit Hall with Poster Viewing |
| Main Conference- DAY THREE Friday, September 26, 2008 | Pre-Conference Workshops | DAY ONE | DAY TWO | | |
| Protein Kinase Targets | |
| 8:30 | Chairperson's Opening Remarks |
| Developing and Examining Effective Therapeutic Approaches | |
| Keynote Presentation | |
| 8:45 | Developing Kinome-Scale Approaches to Understand Cell Signaling and Develop Effective Therapies The 518 human kinases collectively control the vast majority of cellular pathways and so have the potential to both reveal the behavioral state of any cell and to modulate those behaviors. Integrated genomic, evolutionary, pathway and experimental analysis of the kinome highlights many novel drug targets, the core functions of hundreds of kinases, the functional impact of SNPs and somatic mutations, and the interdependence of kinase-modulated pathways for combination therapies and overcoming drug resistance. Gerard Manning, Ph.D., Staff Scientist, The Salk Institute |
| 9:30 | Structural Biology & Functional Enzymology Studies of KIT Wild-type & Mutated Proteins Elucidate the Binding and Resistance Mechanisms of Sunitinib in GIST Patients The efficacy of kinase inhibitors imatinib mesylate and sunitinib malate in gastrointestinal stromal tumor (GIST) patients is mainly through the inhibition of mutant KIT proteins. Sunitinib has been shown to be effective against certain imatinib-resistant mutants, although a subset of imatinib-resistant mutants is also resistant to sunitinib. Biochemical, biophysical and structural biology studies were undertaken to elucidate the resistance mechanisms. Elizabeth Lunney, M.S., Research Fellow, Pfizer Global Research & Development |
| 10:00 | Technology Workshop There are a limited number of technology workshop slots available. Please contact Jennifer McElligott at jmcelligott@ibcusa.com or 508-614-1672 for additional information. |
| 10:30 | Networking Refreshment Break in Exhibit Hall with Poster Viewing |
| Structure and Non Classical Site Binding | |
| 11:00 | Kinase Switch Pockets: Targeting Non-ATP Pockets in Kinases This lecture will highlight the attributes of targeting kinase conformational switch pockets by demonstrating its application to kinases such as p38, BCR-Abl and B-raf kinases. Drug discovery programs directed at these kinases have been guided extensively by iterative structure-based design. The BCR-Abl program has afforded potent development candidates that inhibit the unphosphorylated form, phosphorylated forms, and various mutants of BCR-Abl kinase including the T315I mutant clinical isolate form that is resistant to Gleevec and dasatinib. The B-Raf program has afforded sub-nanomolar inhibitors of V600E B-Raf kinase as well as inhibitors of the T592I gatekeeper mutation within the background of mutant V600E B-Raf. The p38 program has resulted in inhibitors that spare the rest of the kinome. The role of structure in advancing small molecule potency and selectivity will be discussed. Peter A. Petillo, Ph.D., Senior VP and Chief Scientific Officer, Deciphera Pharmaceuticals |
| 11:30 | Crystal Structures of Plk1 and Applications to Drug Design Polo-like kinase 1 (Plk1), a key mitosis regulator whose overexpression is observed in a variety of cancers, is an attractive target for the development of anticancer agents. Several Plk1 inhibitors that are in clinical trial exhibit nanomolar cellular potency against Plk1 isoforms and good selectivity against non-Plk kinases. This talk will present structures of Plk1 with accompanying biochemical data, analyze structure-activity relationships of known Plk1 inhibitors and discuss key features in designing Plk1 specific therapeutics. Yaun-Hua Ding, Ph.D., Research Scientist, Pfizer Inc. |
| 12:00 | Non Classical Site Binding Audience Discussion The mechanism through which kinase inhibitors traditionally operate is by association with the adenosine binding site at the kinase hinge region and extending into other areas of the active site to increase potency and selectivity. There are a few examples of inhibitors classes, such as the allosteric MEK1 compounds, the "phe-out" inhibitors, and the switch pocket regulators, that work by alternative inhibitory mechanisms. We'll have a group discussion focused on the viability of exploiting these inhibitory mechanisms for drug discovery. Lead by: Scott Jakes, Ph.D., Director, Department of Cardiovascular Diseases, Boehringer Ingelheim Pharmaceuticals Inc. |
| 12:30 | Protein Kinase Conference Ends Networking Luncheon in Exhibit Hall with Poster Viewing |
| Assay & Screening Advances | |
| 8:45 | Chairperson's Opening Remarks |
| Examining Future and Current Screening Approaches | |
| 9:00 | A Cellular Systems Biology Approach Cellular Systems Biology methods have been created to accelerate identification and optimization of novel lead series, including biosensors for protein:protein interactions, that when coupled with assays for multiple biomarkers, capture the cellular systemic response to drugs. This approach enables identification of series expressing the requisite (multi)-target activity profile while simultaneously monitoring off-target toxicities. Kate Johnston, Ph.D., Vice President, Discovery Programs, Cellumen Inc. |
| 9:30 | High Throughput Approaches to Systems Biology Screening Rather than solely studying, or screening against individual cellular components for novel targets/therapeutics, a more systems biology approach to cellular screening is evolving which largely results from our growing understanding of the genetic constitution of life. New tools, technologies and methodologies now enable scientists to delve deeper into the complex foundations of biological activity and thoroughly probe efficacy, mechanism of action and toxicity of potential therapeutic agents in a higher throughput environment. Sarah Payne, Ph.D., Marketing Director, TTP LabTech Inc. |
| Technology Workshop | |
| 10:00 | Cell-Based Screening Approaches for Protein-Protein Interactions Protein-protein interaction measurements are problematic in cell-based screening campaigns because optimal reagents are not available. Positional-based protein-protein interaction biosensors enable measurements of reversible protein-protein interactions in living cells through dynamic changes in their cellular localization. These new reagents have distinct advantages over current technologies, and also enable integration into cellular models of disease. Ken Giuliano, Ph.D., Principal Scientist, Cellumen, Inc. |
| 10:30 | Networking Refreshment Break in Exhibit Hall with Poster Viewing |
| 11:00 | Critical Network Identification and Cancer Drug Design We employ a variety of assays to generate a systems view of molecular signaling in tumor cells. This informs our selection of signaling networks for therapeutic intervention. Computational modeling and simulation is then used to identify the most efficacious mode of network inhibition and to guide cancer drug design. Arthur J. Kudla, Ph.D., Associate Director, Research, Merrimack Pharmaceuticals |
| 11:30 | Using a Dynamic Bayes Approach to Understand Complex Signaling Networks Conventional approaches to learning using statistics and clustering have been undermined by the noisily underlying data from cells and tissues. GNS has developed a learning algorithm approach that takes advantage of the noise in biological systems to provide insights into causal networks that drive complex processes and leverages supercomputers and advanced algorithms to support understanding of the networks driving processes. This provides quantitative hypotheses that can be tested to refine the network structures. This and other results of the network analysis will be discussed. Zach Pitluk, Ph.D., Vice President, Business Development, Gene Network Sciences Inc. |
| 12:00 | High Content Screening as a Tool for Systems Biology Automated imaging and analysis provides a wealth of data from which information and ultimately, biological knowledge may be built. However, the scale and complexity of imaging-derived data often deters its use in high throughput screening. Systems biology aims to use imaging-derived data to develop quantitative models of dynamic multi-scalar biological systems and thus its progress depends on efficient mining and modeling of these large and expanding datasets. James G. Evans Ph.D., Assistant Director, Whitehead MIT BioImaging Center |
| 12:30 | Networking Luncheon in Exhibit Hall with Poster Viewing |
| G-Protein Coupled Receptors | |
| 8:45 | Chairperson's Opening Remarks |
| Computer Modeling and Visualization of GPCR's and Signaling | |
| 9:00 | New Approaches to 3D Modeling of GPCRs We developed several methods, namely the SCARE algorithm and the Ligand-Guided Modeling protocol, that "transform" the 2.4 Å b2 Adrenoceptor (b2AR) crystal structure into specific 3D models of ligand binding and specificity of some key GPCRs. These models were validated and applied to docking or virtual ligand screening for both agonists and antagonists. Ruben Abagyan, Ph.D., Professor, Department of Molecular Biology, The Scripps Research Institute |
| 9:30 | Real-Time Visualization of G Protein Signaling Heterotrimeric G proteins are dynamic molecules, moving in and out of membrane microdomains that channel their signaling properties. We will focus on methods for real-time imaging of these proteins as they traverse the membrane and internalize to interact with intracellular organelles. The usefulness of fluorescent G proteins for drug screening will also be discussed. Mark M. Rasenick, Ph.D., Distinguished UIC Professor of Physiology & Biophysics and Psychiatry, Department of Physiology & Biophysics, University of Illinois College of Medicine |
| 10:00 | Technology Workshop There are a limited number of technology workshop slots available. Please contact Jennifer McElligott at jmcelligott@ibcusa.com or 508-614-1672 for additional information. |
| 10:30 | Networking Refreshment Break in Exhibit Hall with Poster Viewing |
| Implementation of GPCR Technology Advancements | |
| 11:00 | Pros and Cons of Using New GPCR Technologies in Drug Discovery: A Lundbeck Perspective Drug discovery and development require the use of sensitive and selective cell-based assays. Recently, a growing number of technologies such as the label free, aequorin and β-arrestin assays have emerged as an alternative to standard FLIPR based assays. We will review our results and experience working with these technologies. Suresh B Poda, Ph.D, Global HTS Center, Biological Research, Lundbeck Research USA, Inc |
| 11:30 | Multiplex Agonist/Antagonist Screening of GPCRs Using Hamamatsu FDSS-7000 Kinetic Plate Reader in 1536-well Plate Format The kinetic assay using fluorescence calcium dye is commonly used in compound screening for Gq coupled GPCRs. However, the kinetic assay in 1536-well plate format is a challenge with the previous instruments. Recently, we have applied a newly available Hamamatsu FDSS-7000 instrument for the GPCR compound screening in 1536 well assay format. It is equipped with two pipetting heads which allows this instrument to dispense compounds and agonist sequentially to the assay plate and washing tips rapidly during the experiment enabling us to perform agonist and antagonist screenings using one assay plate. Ke Liu, Ph.D., Staff Scientist II, NIH Chemical Genomics Center |
| 12:00 | A Bioluminescent Biosensor for Real-Time Monitoring of Intracellular cAMP Bioluminescent assays are uniquely suited for developing cell-based assays, especially for high-throughput screening, due to their inherently high sensitivity, wide dynamic range and low susceptibility to compound interference. Here we present novel bioluminescent assays using a genetically encoded biosensor designed to rapidly interrogate cAMP levels in living cells. The biosensor is based on a circularly permuted form of firefly luciferase into which a cAMP-binding domain is inserted. These assays 1) allow for non-lytic, real-time monitoring of intracellular cAMP in live cells, 2) can be readily used to study GPCR modulation, and 3) are highly amenable for high-and ultra high-throughput screening. Kevin Kopish, Global Product Manager, Cellular Analysis, Promega Corporation |
| 12:30 | GPCR Conference Ends Networking Luncheon in Exhibit Hall with Poster Viewing |
| Ion Channel Targets | |
| 8:30 | Chairperson's Opening Remarks |
| Sodium Channel Advances | |
| Keynote Presentation | |
| 8:45 | Voltage Gated Sodium Channels: Molecular Machines for Electrical Signaling and Novel Drug Targets Voltage gated sodium channels initiate action potentials in nerve and muscle, but the mechanism of their voltage gating is unresolved and their promise as drug targets is unfulfilled. This opening lecture will present new results on the structural basis of voltage-dependent activation of sodium channels and provide an overview of sodium channel molecular pharmacology. William Caterall, Ph.D., Professor and Chair, Pharmacology, University of Washington |
| 9:30 | Nav1.7 Mutations associated with Neuropathic Pain Inherited disease mutations in Nav1.7, a voltage-gated sodium channel highly expressed in peripheral neurons, have been associated with complete inability to sense pain and two distinct neuropathic pain disorders. Understanding how gain-of-function mutations that cause severe neuropathic pain alter Nav1.7 activity provides important insight into how sodium channels can contribute to more common types of pain. Theodore R Cummins, Ph.D., Assistant Professor, Pharmacology & Toxicology, Stark Neurosciences Research Institute, Indiana University School of Medicine |
| 10:00 | Technology Workshop There are a limited number of technology workshop slots available. Please contact Jennifer McElligott at jmcelligott@ibcusa.com or 508-614-1672 for additional information. |
| 10:30 | Networking Refreshment Break in Exhibit Hall with Poster Viewing |
| 11:00 | Discovery and Development of Conopeptide-Based Analgesics that Target Neuronal Subtypes of Sodium Channels Peptide-based neurotoxins from venomous cone snails continue to provide analgesic compounds; several have already reached human clinical trials. Recently, we discovered a new group of conopeptides that potently and selectively block neuronal subtypes of sodium channels, and are potent analgesics following systemic administration. Discovery, biochemical and pharmacological properties of these conopeptide-based analgesics and second-generation lead compounds will be discussed. Grzegorz Bulaj, Ph.D., Assistant Professor, Department of Medicinal Chemistry, College of Pharmacy, University of Utah |
| Ion Channel Technology Advancement Case Studies | |
| 11:30 | Case Study - Screening Ion Channels for Safety and Efficacy We are developing a library of ion channel-expressing cell lines for screening with the full range of automated patch clamp instruments and FLIPRTetra®. At present, 86 "books" are available and 160 will be available by June 2009. Each cell line is validated for cDNA sequence, Western blot, voltage range, gating and pharmacology. Ion channels are mixed and matched into panels according to tissue, e.g., cardiac; therapeutic area, e.g., pain; and ion channel family, e.g., TRP channels. Arthur M. "Buzz" Brown, M.D., Ph.D., President & CEO, ChanTest Corporation |
| 12:00 | Case Study - Development of a QPatch Platform for Purinergic Ion Channels For small molecule drug discovery programs, planar patch clamp platforms can provide an important link between HTS and standard electrophysiological methods generally employed in the lead optimization process. In order to streamline the screening cascade for our purinergic ion channel antagonist programs, we have recently developed Sophion QPatch assays for multiple P2X channels. These assays provide high quality data for elucidating SAR with the capacity and turnaround sufficient to rapidly advance novel small molecule development. Furthermore, they are easily transferred to staff with minimal training in patch clamp methods. Assay development challenges including cell line creation, preparation, patch clamp parameters, and pharmacological results will be discussed. Paul H. Reynen, Research Scientist II, Evotec USA |
| 12:30 | Networking Luncheon in Exhibit Hall with Poster Viewing |
| Assay & Screening Advances | |
| 2:00 | Chairperson's Remarks |
| Keynote Presentation | |
| 2:15 | An In Vitro Systems Approach to Predicting and Understanding Clinical Responses to Molecularly Targeted Therapeutics We are developing methods that allow targeted treatment of individual cancer patients by using in vitro models of response to identify molecular signatures that predict clinical utility. The panel of cell lines reflects the substantial heterogeneity of breast cancers at the genomic and transcriptional levels. Traditional growth assays are used to assess cell line responses to individual agents and are then compared to the mutational spectra, copy number aberrations, and transcriptional profiles to identify predictors of response. These predictors can then be deployed clinically to determine which patients are likely to benefit from a given agent. Paul Spellman, Ph.D., Staff Scientist, Lawrence Berkeley Lab |
| Primary Tissue and Stem Cells in Screening | |
| 3:00 | Chromosomal Targeting in Embryonic Stem Cells Using the phiC31 Family of Integrases: hESCs as Enabling Tools for Screening One of the biggest obstacles to using human embryonic stem cells in the generation of assay platforms is the difficulty in achieving stable, homogeneous expression of lineage reporters and cell perturbation constructs in these cells in culture. Our group is working towards developing genetically engineered hESC lines as a unique platform that will enable isolation of homogenous populations of cells containing multiple genetic elements inserted in a single, defined chromosomal locus. We are also working toward optimizing differentiation of pre-engineered hESCs and developing isolation protocols to create high content cell based assays in 'primary' tissues. These approaches and other stem cell screening advances will be discussed. Jonathan D. Chesnut, Ph.D., Director, Stem Cells and Regenerative Medicine, Invitrogen |
| 3:30 | Networking Refreshment Break |
| 4:00 | BioMAP Primary Human Cell-Based Systems for Drug Discovery Bridging the gap between molecular target discovery and human pharmacology will improve our ability to identify safe and effective therapeutics. BioSeek's BioMAP platform uses primary human cell-based disease models to broadly assess drug action and provide a better understanding of drug mechanisms relevant to disease and tissue biology. Examples of successful mechanism of action identification and applications for predictive toxicology will be presented. Ellen L. Berg, Ph.D., Chief Scientific Officer, BioSeek, Inc. |
| 4:30 | High Content Tissue Screening Cell behavior can change drastically when a cell is removed from its native 3D tissue environment. Many processes such as angiogenesis, fibrosis, and cancer cannot be studied effectively when interactions with the tissue stroma are absent. We describe advances in high speed, microscopic imaging and labeling that are enabling next generation assays based at the physiologically, disease relevant, tissue level. Timothy Ragan, Ph.D., President, TissueVision, Inc. |
| 5:00 | Conclusion of ACT 2008 |
| Ion Channel Targets | |
| 2:00 | Chairperson's Remarks |
| Novel Ion Channel Applications | |
| 2:15 | Novel Role of TRP Channels: Regulators of the Function of Pancreatic Cells In pancreatic ατεβ-cells, glucose stimulates insulin secretion by a sequence of events that involve glucose uptake and metabolism, an increase in cellular ATP that closes ATP-sensitive K+ channels, membrane depolarization, and opening of voltage-operated Ca2+ channels (VOC). This process involves oscillations in electrical activity and changes in [Ca2+]i. Several ion channels of the transient receptor potential melastatin (TRPM) ion channel family have been identified in ατεβ-cells and they may also participate in beta cell function. While the Ca2+-activated TRPM4 channel has been proposed to regulate electrical activity, ADP-ribose-gated TRPM2 channels and Mg-nucleotide regulated TRPM7 channels may serve roles in apoptosis and cell survival. The contributions of TRPM channels to pancreatic ατεβ-cell function will be discussed. Reinhold Penner, M.D., Ph.D., Professor of Cell & Molecular Signaling, University of Hawaii |
| 3:00 | Inhibitors of CLC chloride channels CLC chloride channels are potential targets for diverse therapies, yet no specific, high-affinity modulators have yet been identified. Recently, we have discovered that hydrolysis products of the non-specific anion-transport inhibitor DIDS are the most potent CLC inhibitors yet reported. Merritt Maduke, Ph.D., Assistant Professor, Stanford University |
| 3:30 | Networking Refreshment Break |
| 4:00 | HCN Channels as Drug Targets Hyperpolarization- and Cyclic Nucleotide-gated (HCN) channels are a family of six transmembrane domain, single pore-loop, hyperpolarization activated, non-selective cation channels. The HCN family consists of four members (HCN1-4). HCN channels represent the molecular correlates of Ih , a hyperpolarization-activated current best known for its role in controlling heart rate and in the regulation of neuronal resting membrane potential and excitability. Evidence is now emerging to support a role for these channels in the function of sensory neurons and pain sensation, particularly pain associated with nerve or tissue injury. As such, HCN channels may represent valid targets for novel analgesic agents. Michael Maher, Senior Scientist, Drug Discovery, Johnson & Johnson PRD |
| 4:30 | Novel Activators of Small and Intermediate-Conductance Calcium-Activated Potassium Channels Based on the Neuroprotectant Riluzole The neuroprotectant riluzole activates small- and intermediate-conductance Ca2+-activated K+ channels at 2 to 20 microM. Using rilzuole as a template we designed SKA-31, which activates KCa2 and KCa3.1 channels with EC50s of 2 microM and 260 nM. SKA-31 exhibits anticonvulsant effects in the NIH Anticonvulsant Screening Program and lowers blood pressure in mice by increasing the EDFH response. Heike Wulff, Ph.D., Associate Professor, Department of Pharmacology, University of California, Davis |
| 5:00 | Conclusion of ACT 2008 |
Copyright IBC Life Sciences, a part of Informa Life Sciences Group | Global Information, Inc. - International Marketing Partner of IBC Life Sciences