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WEDNESDAY, OCTOBER 22
7:30 Continental Breakfast Breakout Discussion Sessions
Table 1: Correlating in vitro Potency with in vivo Efficacy for Ion Channel Modulators
Moderator: TBA
Table 2: Primary Cell Lines and Automated Patch Clamp Systems for Screening
Moderator: Dinah Misner, Associate Director, Discovery and Investigative Safety, Roche Palo Alto
Table 3: Outside the Box: Are There Non-Conventional Ways for Ion Channel-Based Drug Discovery?
Moderator: Chuan-Chu Chou, Ph.D., Fellow, Schering Plough Research Institute
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ION CHANNEL CARDIAC SAFETY ASSAYS
8:30 Chairperson’s Remarks
Chuan-Chu Chou, Ph.D., Fellow, Schering Plough Research Institute
8:40 Strategies to Predict QT Prolongation and Arrhythmias: Assessing hERG and Other Cardiac Ion Channels Early in Drug Development
Dinah Misner, Associate Director, Discovery and Investigative Safety, Roche Palo Alto
Preclinical strategies to assess new chemical entities (NCEs) for cardiovascular liabilities early in the development process, with an emphasis on detection of QT prolongation and arrhythmias, will be presented. Topics to be discussed include an overview of the current regulatory guidelines around pre-clinical cardiovascular assessment, discussion of state-of-the-art technologies for in vitro testing (specifically around ion channels) and translation to in vivo results, and development of customized strategies to de-risk cardiovascular liabilities of NCEs. Additionally, specific examples will be provided where these new technologies have benefited projects to identify liabilities early, enabling selection of the “best” NCE moving forward.
9:10 Addressing the Challenges in Recombinant Expression for Higher Throughput Screens of Ion Channels with Cardiac Liability
Mao Xiang Chen, Ph.D., Biological and Cellular Targets, BR&AD, GlaxoSmithKline Research and Development
Ion channels of the cardiac action potential, particularly hERG, arguably carry the biggest liability in drug development. Recent years have seen the advent of a number of assay technologies which enabled higher throughput early profiling of individual cardiac ion channels. However, the data quality and throughput obtained with these platforms is critically dependent on the robustness of the expression reagent being used. The generation of high quality, recombinant cell lines and optimization of expression is therefore a key step in developing these assays and this can present significant challenges due to the diversity and organizational complexity of many channel types. This presentation focuses on several difficult to express cardiac ion channels, and demonstrates improved assays can be obtained by integration of expression and optimization strategies with planar array electrophysiology systems.
9:40 Networking Coffee Break in the Exhibit Hall
TARGETING ION CHANNEL MODULATORS OR
AUXILIARY SUBUNITS – AN EXCITING ROUTE
10:35 Chairperson’s Remarks
Chuan-Chu Chou, Ph.D., Fellow, Schering Plough Research Institute
10:40 Functional Modulation of AMPA Receptors by Auxiliary Subunits, TARPs
Akihiko S. Kato, Ph.D., Research Scientist, Neuroscience Discovery Research, Eli Lilly and Company
Many ion channels comprise principal and auxiliary subunits. Auxiliary subunits are effective drug targets, e. g. sulfonylureas for SUR subunit of KATP, and gabapentin for α2δ subunit of calcium channels. We will describe TARPs (Transmembrane AMPA receptor Regulatory Proteins) auxiliary subunits of AMPA-type glutamate receptors. TARPs dramatically regulate trafficking and pharmacology of AMPA receptors. Recently, we discovered another family of TARPs, whose regulation is different from conventional TARPs. Understanding of receptor auxiliary subunits provides further dimensions for therapeutic strategies.
11:10 Inhibitors of Ion Channel Accessory Protein Interactions as Novel Therapeutics for Neuropathic and Inflammatory Pain
Loic L'Huillier, Ph.D., Team Leader, Electrophysiology, Lectus Therapeutics, Ltd.
Accessory proteins confer key functional properties to ion channels such as regulation of biophysical properties, and/or channel trafficking. We have identified, through the use of novel protein-protein interaction assays, series’ of compounds that modulate ion channel function through exploiting the interaction between (i) Kv1.1 channels and their regulatory Kvβ1 accessory protein subunits, and (ii) Cav2.2 channels and their regulatory Cavβ3 accessory protein subunits. We will present an introduction to the development and performance of robust, high-throughput Kv1.1/Kvβ1 and Cav2.2/Cavβ3 protein-protein interaction assays demonstrating the identification of novel series of ion channel modulators. We will also present subsequent functional in vitro electrophysiological characterization and in vivo evaluation of these novel ion channel modulators in models of inflammatory and neuropathic hyperalgesia.
EMERGING ION CHANNEL TARGETS
FOR TREATING TYPE II DIABETES
11:40 Regulation of Glucose Metabolism by the Voltage-Gated Potassium Channel Kv1.3 and the Intracellular Calcium Sensor Synaptotagmin-7
Gary Desir, M.D., Professor, Department of Medicine, Section of Nephrology, Yale University School of Medicine
The voltage-gated potassium channel Kv1.3 plays a key role in the regulation of peripheral glucose metabolism. Channel inhibition in adipocytes leads to membrane depolarization, calcium release from intracellular stores, increased intracellular calcium, and ultimately to GLUT4 translocation to the plasma membrane. Channel deletion results in constitutive expression of GLUT4 at the plasma membrane. Synaptotagmin-7 (Syt-7) also modulates peripheral glucose homeostasis through its action on both insulin secretion and GLUT4 traffic. Syt-7 deletion in mice leads to a diabetic state characterized by decreased insulin secretion by the pancreatic b cell, constitutive expression of GLUT4 at the plasma membrane, and decreased responsiveness to insulin in adipocytes. Since Kv1.3 modulates intracellular calcium, Syt-7 senses intracellular calcium, and are both expressed on GLUT4 vesicles, we speculate that Kv1.3 and Syt VII are components of the machinery that regulates calcium-dependent GLUT4 traffic and glucose metabolism.
12:10 Kv1.3 Channels as Targets for Genetic-Induced Obesity and Intranasal Insulin Delivery
Debra Fadool, Ph.D., Department of Biological Science, Programs in Neuroscience and Molecular Biophysics, The Florida State University
Previously, it has been demonstrated that mice with Kv1.3 gene-targeted deletion (Shaker subfamily of ion channels) fail to gain weight when placed on a high-fat diet and have increased peripheral insulin sensitivity via augmentation of GLUT4 translocation to the plasma membrane. We now show that channel deletion in a genetic model of obesity and late-onset diabetes (MC4R-null mice) reduces body weight by decreasing fat deposition and subsequent fasting leptin levels, significantly extends lifespan and increases reproductive success, and abrogates obesity by increasing locomotor activity and mass-specific metabolism. Intranasal insulin delivery (IND; inhaled insulin) to awake, wild-type mice robustly phosphorylates the channel in the olfactory bulb and increases protein-protein interactions with receptor tyrosine kinases and adaptor proteins that regulate channel biophysics. IND-treated mice had an increased short- and long-term object memory recognition, increased anxiolytic behavior, and an increased odor-discrimination using an odor habituation protocol but no change in odor threshold using a two-choice paradigm. Unlike Kv1.3 gene-targeted deletion that alters metabolism, adiposity, and axonal targeting to defined olfactory glomeruli to generate a “super-smeller” phenotype, suppression of Kv1.3 via IND had no effect on olfactory anatomy that would predict changes in odorant coding.
12:40 Close of Ion Channels Conference