CHI'S DISCOVERY ON TARGET

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2007 Final Agenda

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Wednesday, October 25

Shared Program Day with Chemogenomics

7:00 am Registration and Morning Coffee

7:30 Breakfast Workshop (Sponsorship Available)

KEYNOTE SESSION

8:30 Keynote Introduction
	8:40 Target Discovery: Seeking Innovation and the Role of Collaboration with Biotech and Academia Jeremy Levin, D. Phil, MB. Bchir, Global Head, Business Development and Strategic Alliances, Novartis

	9:10 Reducing Clinical Attrition through Efficiencies in Discovery Joseph Bolen, Ph.D., Senior Vice President, Research & Drug Discovery, Millennium Pharmaceuticals

9:40 Coffee Break in the Exhibit Hall

DIFFERENT PERSPECTIVES

10:30 Chairperson: Birgit T. Priest, Ph.D., Senior Research Fellow, Department of Ion Channels, Merck Research Laboratories

Featured Presentations

10:30 Genotype-Selective Compounds for Cancer and Neurodegeneration
Brent R. Stockwell, Ph.D., Assistant Professor, Department of Biological Sciences and Department of Chemistry, Columbia University
We have developed high-throughput cell-based screens that identify small molecules with genotype-selective activity. In one case, we have identified small molecules that are selectively lethal to tumor cells harboring oncogenic RAS. In a second case, we have discovered small molecules that selectively prevent mutant-huntingtin-induced apoptosis. We are using chemical synthesis, affinity purification and mass spectrometry to identify protein targets of such compounds, illuminating mechanisms for achieving such genotype-selective modulation of cell death mechanisms.

11:05 E-VIPR Enables Gene Family Approach to Voltage-gated Ion Channels
Jesus “Tito” Gonzalez, Ph.D., Senior Director, Biology, Vertex Pharmaceuticals
Voltage-gated ion channels regulate many physiological functions and are targets for numerous drugs. Functional assay methods generally used for these targets included: 1) patch-clamp electrophysiology, which is information-rich but laborious and costly; and 2) membrane potential and flux assays which provide high-throughput analysis but relatively little mechanistic information. Here we discuss an electro-optical technology, E-VIPR, that employs extracellular electrical field stimulation and cellular fluorescent probes to measure the activity of voltage-gated ion channels. We demonstrate advantages of this platform that remove important conventional assay constraints and allow large-scale profiling of selectivity, mechanism of action and kinetics of channel modulators. The robustness, sensitivity and flexibility of this technology has potential to provide unprecedented access to voltage-gated ion channel targets.

11:40 Using Chemogenomics Approaches for Novel Target Discovery and Compound Mechanism of Action
Alex Gaither Ph.D., Research Investigator I, Genome and Proteome Sciences Department, Novartis Institutes for Biomedical Research
A three step pipeline has been developed to improve siRNA based target discovery using compounds; an unbiased way to optimize for siRNA delivery into cells, screening small disease relevant subsets of the genome, and incorporating compound treatment as a tool to activate pathways relevant to disease. Using this optimized chemogenomics based approach, combining siRNA and compound screens, we have identified targets that can improve novel and/or preexisting compound therapies. This technology has been systematically applied to many compounds in the pipeline to better understand a small molecule’s activity before moving into the clinic. Chemogenomics provides a way to rapidly assess the value of compounds as therapies through mechanism based siRNA screening.

12:15 Technology Watch (Sponsorship Available)

12:30 Lunch in the Exhibit Hall

Roundtable Buzz Session

2:00
Roundtable: Challenges of Making Selective Ion Channel Modulators
Moderator: Tito Gonzalez, Ph.D., Senior Director, Ion Channels, Vertex Pharmaceuticals, Inc.
Recorder: Birgit T. Priest, Ph.D., Primary Research Fellow, Ion Channels, Merck
Discussion Points:
• Why is selectivity such a challenge?
• How much selectivity is needed and against what targets?
• How can we improve the efficiency of generating selective molecules?

Roundtable: Oral Availabilitiy: Improving Solubility of Lipophilic Candidates
Discussion Points:
• Balance between maintaining potency and pharmacokinetic properties.

Roundtable: Looking Toward TRP, ASICS, and More Recently Identified
Channels: The Future of Ion Channels as Drug Targets
Moderator: Magdalene Moran, Ph.D., Senior Scientist and Director, Target Discovery-Channel Group, Hydra Biosciences
Discussion Points:
• Which of the ion channel families are of greatest interest for drug
   development?
• What indications are best suited to be approached by ion channel
   modulators?
• How does one achieve validation for novel channel targets? How useful are
knockouts?

Roundtable: Screening Entire Libraries Verses Focused Libraries

Roundtable: What does the the future hold for ion channel HTS technologies?

Roundtable: How can we identify and develop ion channel modulators with novel mechanism of action (beyond pore blockers)?

3:30 Refreshment Break in the Exhibit Hall

ION CHANNELS AND SMALL MOLECULE TARGET DISCOVERY

4:00 Chairperson: Alex Gaither Ph.D., Research Investigator I, Genome and Proteome Sciences Department, Novartis Institutes for Biomedical Research

4:10 Development of Novel TRP Channel Antagonists with Analgesic Properties
Magdalene Moran, Ph.D., Senior Scientist and Director, Target Discovery-Channel Group, Hydra Biosciences
We have investigated the role of a TRP channel and its involvement in the transmission of painful stimuli. In order evaluate the role of this channel, Hydra Biosciences has developed a high throughput screen that allowed the identification of selective antagonists. Importantly, these antagonists are highly selective over voltage-gated channels, such as hERG and other TRP channels including the capsaicin receptor, TRPV1. In vivo assessment showed this class of antagonists to be efficacious in several models of pain. To our knowledge, this represents the first example of a selective antagonist to this TRP channel and validates it as a target for the treatment of inflammatory and nociceptive pain.

4:35 Using Worm Genetics to Identify Small Molecule Targets and the Residues Required for Interaction
Peter J. Roy, Ph.D., Assistant Professor, Department of Medical Genetics and Microbiology, University of Toronto
Identifying the protein targets of small bioactive molecules discovered through phenotypic screens is a major bottleneck of generating useful biological probes. Here, we show how C. elegans mutants that are resistant to a small molecule led to the discovery of a novel L-type calcium channel antagonist with unique properties. In addition, we believe that the mutated residues provide novel insights into channel function and interaction with the antagonist. We propose that this approach will be of similar value for other small molecules that have bioactivity in C. elegans.

5:00 Exploring a Focused Library of Novel Kv Channel Active Compounds
Geoffrey W. Abbott, Ph.D., Assistant Professor, Department of Medicine, Cornell University, Weill Medical College
Voltage-gated potassium (Kv) channels control membrane potential, excitability, and action potential morphology and duration. As such, Kv channels represent ideal candidates for therapeutic intervention to prevent abnormal electrical excitability; conversely, inappropriate pharmacological modulation (or mutation) of these channels can generate broad electrical dysfunction, exemplified by inadvertent inhibition of the hERG potassium channel and acquired long QT syndrome. We are adopting a low-throughput approach to explore novel channel-active compounds in a focused library identified by specifying three simple criteria: a modular, expandable structural platform, net positive charge, and lack of effects on hERG. Surprisingly, different compounds within the same structural class act as Kv channel antagonists or agonists depending on subtle structural differences and channel type. Ongoing studies are aimed at identifying the binding sites of existing compounds while developing new compounds based on the most promising structural sub-classes.

5:30 Close of Conference Day

Thursday, October 26

8:30 Conference Introduction

Featured Presentation

8:35 Making Isoform-Specific Channel Blockers Easily? Progress with TRP
David J Beech, Ph.D., Professor, Institute of Membrane & Systems Biology, University of Leeds
Mammalian homologues of Drosophila Transient receptor Potential (TRP) comprise a family of at least 25 calcium- and sodium-permeable channels with broad expression profiles. It is emerging that they have remarkable sensing capabilities, with roles in taste and pain sensation. Importance, however, is not restricted to sensory systems. Our focus has been on vascular smooth muscle cells, known for three decades to have calcium entry mechanisms in addition to the L-type calcium channel. Many of these mechanisms would now seem to be explained by TRP channels: the emerging functions of over ten subtypes will be reviewed. A feature of TRP channels is that many are activated by specific lipids, suggesting a general hypothesis whereby they function as lipid ionotropic receptors. Recently we discovered TRPC5 is activated by the important signaling phospholipids lysophosphatidylcholine and sphingosine-1-phosphate, beginning exploration of the relevance to vascular biology. Determination of relevance is hampered however without isoform-specific blockers, which are largely lacking in the TRP channel field. In an effort to overcome this problem we turned to antibodies. Perhaps surprisingly we find a simple design strategy (referred to as E3-targeting) highly successful, leading to blockers with excellent specificity. One such agent was shown recently to suppress neointimal hyperplasia in a human coronary artery bypass vessel. Further progress will be described.

Targeting Pain

9:05 Chairperson: Michael F. Jarvis, Ph.D., Associate Research Fellow, Neuroscience Research, Abbott Laboratories

9:10 TRPV1 Antagonists as Anti-Hyperalgesics: Role of Differential Pharmacology
Narender Gavva, Ph.D., Senior Scientist, Department of Neuroscience, Amgen, Inc.
TRPV1 is activated by chemical ligands (capsaicin, RTX, anandamide, and protons [pH < 5.7]), components of the inflammatory soup, and heat (>42 ºC), making it a molecular integrator of multiple noxious stimuli. TRPV1 antagonists representing different chemotypes that block all modes of activation produce anti-hyperalgesic effects in models of inflammatory, surgical-incision pain as well as analgesia in cancer pain models. Antagonists of TRPV1 that show differential pharmacology by their interaction through capsaicin-binding pocket were discovered by medicinal chemistry efforts. Mechanism(s) of differential pharmacology and the effects of TRPV1 antagonists that exhibit differential pharmacology on inflammation-induced hyperalgesia will be discussed.

9:40 Purinergic-Gated Ion Channels in Chronic Pain States
Michael F. Jarvis, Ph.D., Associate Research Fellow, Neuroscience Research, Abbott Laboratories
It is now appreciated that ATP functions as a fast neurotransmitter through its interaction with two distinct superfamilies of cell surface receptors, the ligand-gated ion channels (P2X receptors) and G-protein coupled (P2Y) receptors. Recent molecular, neurophysiological, and pharmacological data indicate that specific P2X channel subunits (e.g. P2X3, P2X7, and P2X4) modulate nociceptive signaling. These advances have been greatly facilitated by the discovery of potent and pharmacologically selective antagonists. This presentation will provide an overview of the recent developments in the discovery of novel P2X3 and P2X7 receptor ligands and their use in delineating the contributions of these channels to nociceptive signaling in experimental models of chronic pain.

10:10 Coffee Break in the Exhibit Hall

11:10 Efficacy of Sodium Channel Blockers in the Treatment of Neuropathic Pain
Birgit T. Priest, Ph.D., Senior Research Fellow, Department of Ion Channels, Merck Research Laboratories
Voltage-gated sodium (NaV) channels play a critical role in the initiation and propagation of action potentials. Neuropathic pain in humans and in rodent models is associated with abnormal action potential firing in normally quiescent sensory neurons, and sodium channel blockers have been shown to be efficacious in the treatment of neuropathic pain. Since the use of established sodium channel blockers, such as mexiletine and lamotrigine, is largely limited by adverse CNS effects, reduced CNS exposure may offer an advantage in the development of novel sodium channel blockers. CDA54, a sodium channel blocker with low brain penetration, was more efficacious in rat neuropathic pain models than mexiletine, suggesting that inhibition of peripheral nervous system sodium channels alone is sufficient to confer analgesic efficacy.

11:40 Targeting Neuronal Nicotinic Receptor Subtypes for CNS Diseases
Murali Gopalakrishnan, Ph.D., Project Leader & Associate Volwiler Research Fellow, Neuroscience Research, Abbott Laboratories
Neuronal nicotinic receptors (NNRs) are pentameric ligand-gated ion channels expressed in mammalian central nervous system (CNS) including in regions associated with cognitive processing and pain. Emerging physiological and pharmacological evidence suggest NNR subtypes, such as a4b2 and a7, as potential targets for the treatment of central nervous disorders including pain, schizophrenia and cognitive deficits associated Alzheimer’s disease and other dementias. Accordingly, agonists selectively targeting NNR subtypes have been developed over the years. In addition, positive allosteric modulators at select NNR subtypes such as at the a7 subtype, are known. More recently, pilot human proof-of-concept studies with NNR selective ligands have emerged. This presentation will overview recent developments in the identification and characterization of novel NNR subtype selective ligands with utility for the treatment of CNS diseases.

12:15 Technology Watch

12:30 Technology Workshop (Sponsorship Available) or Lunch on Your Own

NEW TECHNOLOGIES: SCREENING PARADIGMS

2:00 Chairperson: Fredrick Van Goor, Ph.D., Research Fellow I, Vertex Pharmaceuticals

2:05 Development of Ion Channel Targeted Therapies Using Emerging High Throughput Electrophysiology Platforms
Peter Haddock, Ph.D., Team Leader, Ion Channel Group, CNS Biology, Pfizer Inc., PGRD Michigan
Ion channels are abundant in many cell types where they play key roles in regulating cardiac, neuronal, and secretory tissues function. As such, the modulation of ion channel activities may provide a means to impact upon an array of pathophysiological states. A lack of high fidelity, high throughput ion channel screening platforms has previously hindered the full exploitation of ion channels as drug targets. However, new electrophysiological screening technologies are now able to screen large compound libraries and provide structure-activity relationship data to support drug discovery programs. The integration of these technologies into discovery screening paradigms will be discussed and working examples of how they are being used in a large-pharma environment illustrated. Furthermore, the impact of how ion channel functional data is analyzed and reported will be discussed, in particular in relation to the use-dependent nature of ion channel modulators. Pfizer has a strong track record in ion channel drug discovery and this presentation will provide a useful large-pharma perspective on the utility of these new technologies.

2:35 Ion Channel Drug Discovery: Novel Strategies for Targeting Dynamic Proteins
Laszlo Kiss, Ph.D., Research Fellow, Neuroscience Drug Discovery, Automated Biotechnology Group, Merck Research Laboratories
Our knowledge about the structure, function and regulation of ion channels and their role in diseases has increased significantly in the past 20 years. Hence, ion channels have continued to gain pharmaceutical interest as a target class for drug discovery. Ion channels, however, have remained difficult drug targets due primarily to the absence of screening technologies that provide both adequate throughput and high quality of data. Channels are dynamic proteins which can exist in multiple states such as the open, closed and inactivated states. Indirect methods of monitoring ion channel activity (ion flux, binding, fluorescence) do not have the fidelity to distinguish detailed channel kinetics and thus compromise data quality for throughput. Automated patch clamp electrophysiology provides the sensitivity and time resolution required for precise and direct measurement of ion channel activity but is not suitable for HTS. This talk will illustrate how we have integrated the use of established high throughput screening technologies along with recent breakthroughs for automated screening of ion channels and the impact this has made on lead identification and optimization. As a case example, the development of novel antagonists of the Kv1.5 potassium channel and its associated current, IKur, which is observed in the human atrium but not in ventricle, will be presented.

3:05 Design of Ion Channel Targeted Libraries
Markus Haeberlein, Ph.D., Associate Director, Chemistry; Head, Ion Channel Chemistry; AstraZeneca
Heterogeneity in the ion channel family poses an extra challenge to making targeted libraries to this target class. Each ion channel is comprised of several subunits that vary in both number and size. Ligand based information from previously identified ion channel active compounds has been used in the design of the targeted libraries. This activity is part of an initiative to enhance the corporate compound collection, and further directly feeds into the existing portfolio of ion channel drug discovery projects. The approach taken for both ends has been the integration of computational chemistry, parallel synthesis and biological profiling into an effective platform. It will be discussed how this approach has increased hit rates at ion channel targets in HTS and accelerated internal drug discovery programs.

3:35 Refreshment Break in the Exhibit Hall
Enter to win and iPod® nano!
Enter at the CHI registration desk. Winner will be announced in the exhibit hall. You must be present to win.*

Featured Presentation

4:00 Modeling the Structure and Gating Mechanisms of Voltage-Gated Channels
H. Robert Guy, Ph.D., Senior Scientist, Lab of Cell Biology, NCI, NIH
Recently determined crystal structures of potassium channels are very informative, but leave many questions unanswered. For example, most K+ channel structures are from prokaryotes, and for drug development, we need to know the structures of human channels. Also, the only eukaryotic structure that has been determined, Kv1.2, is in an open conformation, and we would like to know how it gates. Our group is using molecular modeling and simulating methods to extend the meager structural data to other channels that are of biomedical interest and to model gating mechanisms. One of our goal is to develop models of most human relatives of K+ channels, including Na+, Ca2+, and Trp channels, in open, resting and transition conformations. We hope that these models will be sufficiently precise and accurate to be useful in structure-based drug design. The presentation will be a progress report of this effort.

TARGETING OTHER INDICATIONS

4:30 Introduction

4:35 KCNN4: An Attractive Target for T Cell-Mediated Autoimmune Diseases and Certain Cancers
Chuan-Chu Chou, Ph.D., Fellow, Inflammation, Schering-Plough Research Institute
KCNN4 is an inducible potassium ion channel in T lymphocytes. Selective blockade of the channel protected mice from developing experimental autoimmune encephalomyelitis (EAE). The treatment did not prevent T cell proliferation or migration, but caused a dramatic reduction in the levels of several pro-inflammatory factors in the CNS. The results suggested that KCNN4 plays a gate-keeping role in inflammation. Consistent with the protecting effect in the EAE model, in a mouse model of collagen-induced arthritis (CIA), selective blockade of KCNN4 delayed the onset and reduce the severity of the disease. As KCNN4 blockers have been shown in the literature to inhibit the proliferation of pancreatic, breast, and prostate tumor cell lines, we confirmed the in vitro cytostatic activity of a KCNN4 blocking compound and extended the studies into a pancreatic cancer-xenograft model. The results indicated that blockade of the channel reduced the growth of the tumor in vivo. Although the mechanisms are still under investigation, our observations suggest that KCNN4 plays a dominant role in T-cell mediated inflammation as well as in the growth of certain cancers.

5:05 Dual Approach to Modulating the PKA-Regulated Chloride Channel Mutant Known to Cause Cystic Fibrosis
Fredrick Van Goor, Ph.D., Research Fellow I, Vertex Pharmaceuticals
Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in cftr, a gene encoding a PKA-regulated Cl- channel (CFTR). The most common mutation results in a deletion of phenylalanine at position 508 (DF508-CFTR) that leads to a reduction in the cell surface density and gating activity of the anion channel. In the airway, these defects alter salt and fluid transport, leading to chronic infection, inflammation, and bronchiectasis. Here we describe two classes of potent small molecules identified by high-throughput screening and medicinal chemistry optimization that restore the cell surface density and gating activity of D508-CFTR in airway epithelia isolated from multiple CF patients. The changes in D508-CFTR activity are sufficient to improve airway epithelial function and support the rationale of a drug discovery strategy based on rescue of the basic genetic defect responsible for CF.

5:35 Close of Conference

*Apple is not a sponsor or participant of this program.

For more information regarding the agenda please contact:
Holly Groelle, Ph.D., Conference Director
Phone: 781-972-5455 Email: hgroelle@healthtech.com

For sponsorship or exhibiting information, please contact:
David Karp, Manager, Business Development
Phone: 781-972-5452,
E-mail: dkarp@healthtech.com

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