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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

 

10:10 Grand Opening Coffee Break in the Exhibit Hall

Structural Studies

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.

Improving Lead Generation

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

Ion Channel Cardiac Safety

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.

 

Emerging Therapeutic Targets

 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, K_Ca2) 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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