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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

 

KEYNOTE SESSION

8:30 Chairperson’s Opening Remarks

Chuan-Chu Chou, Ph.D., Research Fellow, Schering Plough Research Institute

Gregory J. Kaczorowski8:40 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.

 

Dabrowski Michael9:10 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.

 

Clapham David9:40 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

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, 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

Day 1  |  Day 2 |  Short Courses 

 



Suggested Event Package (November 1 – 4):

November 1

Pre-Conference Short Courses:

Targeting GPCRs and Ion Channels with Antibodies (SC2) AND Structure-Based Design of Ion Channels (SC5)

November 2 - 3

Conference:

Ion Channels as Therapeutic Targets – A Flood of Potential for Drug Discovery

November 3 - 4

Conference:

Kinase Inhibitors: Moving from Discovery to Development OR Targeting Diabetes with Novel Therapeutics: Advancing Clinical Candidates

 

Ion Report

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2014 Discovery on Target Brochure  

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PREMIER SPONSORS 

Cellecta 

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SPONSORSHIPS & EXHIBITS 

The exhibit hall was sold out in 2013, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2014, contact:

Jon Stroup
Business Development Manager
781-972-5483
jstroup@healthtech.com 

2014 Discovery On Target CAG 

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CONFERENCES


October 8 – 9

Targeting Epigenetic Readers and
Chromatin Remodelers
 

Targeting the Ubiquitin Proteasome System  

Big Data Analytics and Solutions  

GPCR-Based Drug Discovery  

RNAi for Functional Genomics Screening
– Part 1
 

Protein-Protein Interactions as Drug Targets  

Antibodies Against Membrane Protein Targets
– Part 1
 


October 9 – 10

Targeting Histone Methyltransferases and Demethylases  

Screening Drug Transporter Proteins  

Maximizing Efficiency in Discovery  

GPCR-Targeted Therapeutics  

Genome Editing for Functional Genomics
Screens – Part 2
 

Cancer Metabolism  

Antibodies Against Membrane Protein Targets
– Part 2
 


SYMPOSIUM


October 7

Next Generation Histone Deacetylase Inhibitors  


SHORT COURSES


October 7

SC1: Designing Scalable Software Systems for Big Data Analytics  

SC2: Approaches for Biologically-Relevant Chemical Diversity  

SC3: Setting Up Effective RNAi Screens: From Design to Data to Validation  

SC4: Targeting Protein-Protein Interactions  

SC5: GPCR Structure-Based Drug Discovery  

SC6: Advances in Metagenomic Drug Discovery for New Anti-Infective Agents  

SC7: Targeting of GPCRs with Monoclonal Antibodies  

SC8: A Primer to Gene Editing: Tools and Applications  

SC9: Introduction to Targeted Covalent Inhibitors  


October 9

SC10: Setting Up Effective Functional Screens Using 3D Cell Cultures  

SC11: Integration of BDDCS and Extended Clearance Principles  

SC12: Introduction to Allosteric Modulators and Biased Ligands of GPCRs  

SC13: Introduction to Drug Metabolism