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TUESDAY, OCTOBER 21
7:00am – 6:30pm Registration Open
7:30 Morning Coffee
PROGRESSING AT AN ACCELERATED
PACE IN ION CHANNEL DRUG DISCOVERY
8:30 Ion Channels as Therapeutic Targets: Minireview & Chairperson’s Remarks
Peter Haddock, Ph.D., Group Leader, Ion Channel Group & CNS Biology, Pfizer
This presentation will review a selected number of recent publications in the field of Ion Channel Biology and Drug Discovery. Dr. Haddock will present a synopsis of several papers in turn that have contributed to the Channel field in the last year and set the stage for the conference to follow.
9:00 Ion Channels as Therapeutic Targets to Modulate Cell Proliferation
George K. Chandy, M.D., Ph.D., Professor, Physiology & BioPhysics, School of Medicine, University of California - Irvine
In 1984, potassium channels were discovered in lymphocytes and shown to regulate lymphocyte activation. Since then, ion channels have been described in diverse non-excitable cells and their role in regulating cell proliferation, transformation and apoptosis is better understood. Ion channels in non-excitable cells are viable therapeutic targets for many diseases. This presentation will highlight two potassium channels, Kv1.3 and KCa3.1, and the blockers we are developing as therapeutics for autoimmune diseases and atherosclerosis
9:35 Improving Ion Channel Lead Generation Capabilities by a Multi-Disciplinary Approach
Michael Dabrowski, Ph.D., Head of Global Ion Channel Initiative, AstraZeneca
We identified a number of scientific and technological gaps impairing the rational pursuit of ion channels as a target class. In order to rectify this situation, identify novel solutions and enable proper ion channel lead generation we employed nine senior postdocorates in chemistry, electrophysiology, molecular and cellular biology. The group works as a team on common themes: Chemistry, Screening Technologies, Assay Refinement and Ion Channel Expression. In this talk several examples of novel solutions and technologies will be presented reflecting how the tractability of ion channels has improved.
10:10 Grand Opening Coffee Break in the Exhibit Hall
10:40 Effective Screening Strategies to Expand the Pharmacology of Ion Channels and Pave the Way for the Next Generation of Ion Channel Therapeutics
Laszlo Kiss, Ph.D., Senior Research Fellow, Merck Research Laboratories
11:10 in-vitro and in-vivo Pharmacology of Novel TRPV1 Antagonists
Anindya Bhattacharya, Ph.D., Senior Scientist, Pain & Related Disorders, Johnson & Johnson Pharmaceutical Research and Development LLC
TRPV1 is a polymodal nociceptor that offers hope as an analgesic drug target. The objective of this presentation will be to review industrial TRPV1 drug discovery efforts including ours, discuss challenges and explore opportunities/benefits of TRPV1 intervention by small molecule antagonists. One of the key focus areas will be to discuss TRPV1 in-vitro screens used during HTS and/or lead optimization with a view of predictability/translatability of the pharmacology to in-vivo efficacy either in a pharmacodynamic or ‘diseased’ model of pathology. Some of the practical issues in a screening paradigm (species difference, recombinant versus native TRPV1, hemi-equilibrium versus equilibrium pharmacology, PK-PD and ADMET) will be presented in context of the continuum of TRPV1 drug discovery.
11:40 PANEL DISCUSSION
Progressing at an Accelerated Pace in Ion Channel Drug Discovery—Meeting the Top Two Challenges:
- Selectivity & Off-Target Effects – Using Technology to Get Past the Bottleneck
- Toward Predictive Pre-Clinical Models for Ion Channels – Translation from in vitro to in vivo
Peter Haddock, Ph.D., Group Leader, Ion Channel Group & CNS Biology, Pfizer
- Anindya Bhattacharya, Ph.D., Senior Scientist, Pain & Related Disorders, Johnson & Johnson Pharmaceutical Research and Development LLC
- George K. Chandy, M.D. Ph.D., Professor, Physiology & BioPhysics, School of Medicine, University of California - Irvine
- Michael Dabrowski, Ph.D., Head of Global Ion Channel Initiative, AstraZeneca
- Laszlo Kiss, Ph.D., Senior Research Fellow, Merck Research Laboratories
- Jesus “Tito” Gonzalez Ph.D., Senior Director, Biology, Vertex Pharmaceuticals, Inc
LEADING-EDGE PHARMACEUTICAL TARGETS
12:10pm High-Throughput Profiling of Ion Channels in Primary Human Cells
Michael Mayer, Ph.D., Department of Biomedical Engineering and Department of Chemical Engineering, University of Michigan
This talk presents a high-throughput method to quantify the functional activity of potassium ion channels in primary human lymphocytes. This method is rapid, automated, specific (here for the voltage-gated Kv1.3 ion channel), and capable of measuring, in parallel, the electrical currents of over 200 individual lymphocytes isolated from freshly drawn blood. The statistics afforded by high-throughput measurements allowed direct comparison of Kv1.3 activity in different subsets of lymphocytes, including CD4+ and CD8+ T cells, γδ T cells, regulatory T cells, and B cells. Moreover, the results suggest that Kv1.3 ion channel activity can be used as a functional activation marker in T cells. High-throughput measurements made it possible to compare the activity of Kv1.3 channels in lymphocyte samples from multiple sclerosis (MS) patients and from rheumatoid arthritis (RA) patients with lymphocyte samples from healthy control subjects. We show that patients with progressive forms of MS have significantly increased Kv1.3 activity in peripheral T cells compared to controls. In the context of RA, preliminary data demonstrate that Kv1.3 activity may be a better biomarker for disease activity than existing markers such as C-reactive protein. We propose that profiling ion channel activity in primary human cells presents an enabling methodology that may be useful for diagnostic applications, therapeutic monitoring, drug screening, and drug safety testing.
12:40 Sponsored by
Development And Validation Of Compound Profiling Assays For Voltage-Gated Sodium Channels Using Automated Electrophysiology
Jeff Clare, Ph.D., Director, Ion Channel Group, Millipore
Voltage-gated sodium channel (NaV) inhibitors are an important class of drugs used to treat a variety of indications including arrhythmia, pain, local anaesthesia, epilepsy and bipolar disorder. Despite the indispensable role of NaV channels in mediating action potentials throughout nervous, cardiac and muscle tissues, drugs that inhibit these channels are remarkably well tolerated. This is thought to be largely due to their voltage- and use-dependent mechanism of action whereby the extent of block is greatly increased during periods of repetitive firing or sustained depolarisation as may occur, for example, during seizure activity or pain signalling. Interest in NaV channels within the pharmaceutical industry has been intensified by the discovery of human mutations in NaV1.7 that confer remarkable inability to sense pain in otherwise healthy individuals. Other subtypes have previously been implicated in pain signalling (e.g. NaV1.8 and 1.3) but, until recently, the development of subtype selective inhibitors has proved extremely challenging and the therapeutic utility of such blockers remains an important issue.This presentation will describe the development and use of a panel of robust assays for profiling the selectivity of compounds against each of the NaV subtypes, from 1.1 to 1.8. These assays use two different automated electrophysiology platforms (Ionworks and PatchXpress) and have been validated for detecting use- and voltage-dependent inhibition.
12:55 Luncheon Technology Workshop (Sponsorship Available) or Lunch on Your Own
1:40 Session Break
LEADING-EDGE PHARMACEUTICAL TARGETS (CON’T)
2:20 Chairperson’s Remarks
Michael Mayer, Ph.D., Assistant Professor, Biomedical Engineering and Chemical Engineering, University of Michigan
2:25 Antagonism of the TRPV1 Channel and Thermoregulation
Nuria Tamayo, Ph.D., Principal Scientist, Amgen
The vanilloid receptor 1 (VR1, TRPV1) is a non-selective cation channel that can be activated by a variety of noxious stimuli, including capsaicin, extracellular acidity and heat. It is expressed in primary afferent neurons and is upregulated following inflammation and nerve injury. Antagonism of this channel is considered an attractive approach for the treatment of chronic pain and inflammatory hyperalgesia. We have recently advanced a TRPV1 antagonist, AMG 517, into clinical trials as a new therapy for the treatment of pain. However, in addition to the desired analgesic effects, AMG 517 significantly increased body core temperature following oral administration. Here we will discuss our two approaches to eliminate or minimize the on-target hyperthermic effect.
2:55 Discovering Small Molecule CRAC Channel Inhibitors
Ken Stauderman, Ph.D., Vice President, Research, CalciMedica
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.
3:25 E Unum Pluribus: One Platform, Three Programs
Arthur M. "Buzz" Brown, M.D., Ph.D., President and CEO, ChanTest Corporation
ChanTest’s 120-member ion channel library (ICL) is being validated and optimized for PatchXpress 7000A, IonWorks Quattro and FLIPRTetra (Automated Patch Clamp-Fluorescence). The single ICL-APC/Fl platform supports three programs: services, supplies and drug discovery. For services, ICL “books” can be arranged for screening according to tissue (Cardiac or CNS Channel Panels), therapeutic area (Pain or Seizure Panels) or channels family (Nav 1.x, Cav x.y). For supplies, “books” are customized by instrument for purchase. For discovery, the ICL-APC/Fl platform can be screened with diversity or ion channel-focused compound libraries or repurposed drug libraries. Examples of the different program applications will be presented
3:55 Networking Refreshment Break in the Exhibit Hall
4:30 Sodium Channel Drug Discovery in the Era of Automated High-Throughput Electrophysiology
Neil A. Castle, Ph.D., Director of Biology, Senior Research Advisor, Icagen Inc.
Voltage-Gated sodium channels are excellent targets for development of drugs to treat neuroexcitatory disorders like pain and epilepsy. Identifying novel drug candidates has historically been a challenge due in part to the complex structural conformational changes that occur during Na channel gating, and the fact that many compounds only interact with specific gating states. The development of high-throughput planar patch clamp electrophysiology technologies like the PatchXpressTM and more recently the Ionworks QuattroTM have provided opportunities to effectively use automated electrophysiology in the hit and lead identification stages of sodium channel drug discovery. In this presentation we will describe how we use both of these platforms to support target and assay development, as well as screening and hit to lead progression.
5:00 Voltage-gated Sodium Channels as Targets for Pain Treatment
Alexander Binshtok, M.D., Instructor in Anaesthesia, Harvard Medical School
5:30 Panel Discussion with Speakers
6:00 Happy Hour in the Exhibit Hall
7:30 End of Day