Day 1 | Day 2 | Short Courses | Download Brochure
|SUNDAY, NOVEMBER 1
Recommended Short Courses*
12:00 pm - 3:00 pm Targeting GPCRs and Ion Channels with Antibodies (SC2)*
3:30 pm - 6:30 pm Structure Based Design of Ion Channels (SC5)*
*Separate Registration Required
MONDAY, NOVEMBER 2
7:00 am Registration and Morning Coffee
8:30 Chairperson’s Opening Remarks
Chuan-Chu Chou, Ph.D., Research Fellow, Schering Plough Research Institute
8:40 The Challenges of Targeting Ion Channels for Therapeutic Benefit
Gregory J. Kaczorowski, Ph.D., Adjunct Professor, Physiology and Pharmacology, New Jersey Medical School; Adjunct Professor, Physiology and Biophysics, Robert Wood Johnson Medical School
Ion channels are important targets of therapeutic agents. Historically, it has been challenging to develop drugs on this target class. A major issue with target based ion channel drug development is identification of good small molecule chemical leads for Medicinal Chemistry optimization to clinical candidate status. Recently, many unique strategies have been developed for ultra high throughput screening of ion channel targets to identify tractable chemical leads in large sample collections. These efforts have been successful in identifying novel modulators of voltage-dependent sodium, calcium and potassium channels. A number of case histories addressing the design and implementation of these novel approaches will be presented.
9:10 Lead Generation and Postdocs in the Pharmaceutical Industry – Lessons Learned
Michael Dabrowski, Ph.D., Head, Global Ion Channel Initiative, AstraZeneca R&D
In 2007, AstraZeneca launched an internal Global Ion Channel Initiative with the aim to fill the gaps in ion channel lead generation. We recruited 9 postdoctoral fellows in electrophysiology, chemistry and molecular cell biology and invested in relevant technologies focusing on ion channel lead generation: e.g. new ion channel targeted chemical libraries, new and better assay formats on existing technology platforms and cutting edge gene delivery and expression systems. In my talk I will show results obtained by the postdoc team improving ion channel lead generation capabilities and also discuss the use of postdocs in this Big Pharma initiative.
9:40 Ion Channel Drug Targets
David Clapham, M.D., Ph.D., Aldo R. Castañeda Professor of Cardio-vascular Research, Investigator, Howard Hughes Medical Institute
10:10 Grand Opening Coffee Break in the Exhibit Hall
10:40 Expression and Purification of Human TRPV1 for Structural Studies
Alla Korepanova, Ph.D., Department of Structural Biology, GPRD, Abbott Laboratories
High-yield heterologous protein production has been a major limiting step in structural characterization of membrane proteins including ion channels. TRPV1 is a ligand-gated ion channel that is involved in acute thermal nociception and neurogenic inflammation. Full-length human TRPV1 was expressed in HIfgh-Five insect cells using the baculovirus expression system. Efficient solubilization and purification procedures resulted in milligram amounts of detergent-solubilized channel at 80 -90% purity. Protein functionality was confirmed by ligand binding. Developed methods can be applied to other TRPV1and mammalian ion channels.
11:10 Structural Insights into the Function of TRPV Channels
Rachelle Gaudet, Ph.D., Associate Professor, Department of Molecular and Cellular Biology, Harvard University
This presentation will describe insights into the function of TRPV channels gained through crystallography, biochemistry and electrophysiology. In particular, the cytoplasmic ankyrin repeats of thermosensitive TRPV channels regulate the sensitivity of TRPV channel responses to multiple stimuli. Both nucleotides and calmodulin interact with the ankyrin repeats and mediate the channel response to changes in cytoplasmic calcium levels.
11:40 Negotiation of HERG Liabilities via a 3D in silico Model: A Case Study
Mark Slack, Ph.D., Senior Scientist, Cellular Assays, Evotec, AG
Numerous clinical projects have been delayed or stopped due to safety pharmacologically issues associated with the hERG ion channel. Anti-histamines have a history of such negative effects on hERG and thus in the development and optimization of potent Histamine receptor 3 (H3) antagonists. Is was desirable to address these liabilities early in the chemical optimization. Within the medicinal chemistry optimization of key H3 scaffolds, carefully selected compounds were analyzed in electrophysiological measurements for their apparent hERG inhibition. The resulting 3D computational model supported the medicinal chemistry to optimize affinity to the H3 target while avoiding hERG liability. In the presentation, the benefits of the approach for the lead series will be shown.
12:10 pm Hits Validation Using Endogenous Ion Channels Expressed on Human CD4+ T Cells
Melisa Ho, Ph.D., Senior Research Scientist, Wyeth Research
12:40 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
2:20 Chairperson’s Remarks
2:25 Cardiovascular Arrhythmia Safety in Drug Development, Inhibition of the Late Ina Current to Stabilize Ventricular Repolarization, and Late Ina as a Therapeutic Target
Albert M. Kim, M.D., Ph.D., Senior Translational Medicine Expert, Cardiac Electrophysiology/Cardiovascular Discovery, Novartis Institutes for BioMedical Research, Inc.
There have been major advances in the evaluation of cardiac safety during drug development and the understanding of ionic mechanisms to destabilize and stabilize ventricular repolarization. This 2 part presentation will cover the major aspects of CV arrhythmia evaluation during drug development, the impact of preclinical data on the early clinical trials, and new research findings, focusing on the Late Ina current, to stabilize ventricular repolarization. Recent data has shown that inhibition of Late Ina can prevent arrhythmogenesis, even in the setting of administration of an arrhythmogenic drug such as one that inhibits hERG. In addition, therapeutic implications of modifying the Late Ina current will be discussed.
2:55 Ion Channels as Lipid Mediators in Brain Diseases
David R. Harder, Ph.D., Associate Dean, Research, The Medical College of Wisconsin
3:25 GW542573X – a Novel, Selective Activator of hSK1 Small Conductance Ca2+-Activated (SK) K+ Channels
Derek J. Trezise, Ph.D., Director, European Discovery Services, Essen Instruments
Ca2+-activated K+ channels are critical regulators of diverse cell functions ranging from neuronal excitability, erythrocyte volume, smooth muscle contraction and lymphocyte activation. Elucidating the physiological roles of specific channel isoforms is, however, hampered by a paucity of selective pharmacological agents. Here we describe a new small molecule, GW542573X, as a selective activator of small conductance Ca2+-activated K+ (SK, KCa2) channels and distinguished from previously published positive modulators of SK channels, such as 1-EBIO and CyPPA, in several aspects. GW542573X is the first SK1-selective compound described: an EC50 value of 8.2 ± 0.8 µM was obtained from inside-out patches excised from hSK1-expressing HEK293 cells. Whole-cell experiments showed that hSK2 and hSK3 channels were >10-fold, and hIK channels > 100-fold less sensitive to GW542573X. The Ca2+ response curve of hSK1 was left-shifted from an EC50(Ca2+) value of 0.41 ± 0.02 µM to 0.24 ± 0.01 µM in the presence of 10 µM GW542573X. In addition to this positive modulation, GW542573X activated SK1 in the absence of Ca2+ and induced a 15% increase in the maximal current at 10 µM Ca2+. Thus, GW542573X also acts as a genuine opener of the hSK1 channels, a mechanism of action not previously obtained with SK channels. Using an SK1 /SK3 channel chimera strategy, followed by site directed mutagenesis, a single amino acid (S293) located in TM5 of hSK1 was found to be essential for GW542573X activation. Substituting the corresponding L476 in hSK3 with serine conferred hSK1-like potency (EC50 = 9.3 ± 1.4 µM). This indicates that GW542573X activates SK1 channels via an interaction with ‘deep-pore’ gating structures at the inner pore vestibule or the selectivity filter, in contrast to 1-EBIO and CyPPA that exert positive modulation via the calmodulin binding domain. GW542573X should prove a useful tool for probing the physiological and patho-physiological roles of SK1 channels.
3:55 Networking Refreshment Break in the Exhibit Hall
4:30 Calcium Channelopathies in Neurological Diseases
Philippe Lory, Ph.D., Institut de Génomique Fonctionnelle, Département de Physiologie, CNRS
Childhood absence epilepsy, familial hemiplegic migraine, episodic ataxia type 2 and autism spectrum disorder are rare inherited forms of common neurological disorders. The genetic basis of these calcium channelopathies provides unique opportunities to study the underlying mechanisms from the molecular to organism levels. Studies of channelopathies illuminate relationships between channel structure and function, and reveal diverse and unexpected physiological roles for these channels. Importantly, these studies also lead to screening for drugs to prevent acquired channel disorders, as well as to novel therapeutic practices.
5:00 Sponsored Presentation (Opportunity Available)
5:15 Ion Channels in Metabolic Diseases
Chuan-Chu Chou, Ph.D., Research Fellow, Schering Plough Research Institute
Ion channels play dominant roles under many pathophysiological conditions, including cardiovascular disorder, pain, and respiratory diseases. Despite the fact of over $6 billion in sales per year the market for ion-channel modulators remains under-exploited. Diabetes represents one of the largest global therapeutic demands and a top challenge to the pharmaceutical industry. This presentation will focus on ion channels as an emerging class of therapeutic targets for diabetes. Several lines of promising experimental evidence and their relevance to the disease in humans will be discussed.
5:45 Happy Hour in the Exhibit Hall
7:00 Close of Day
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