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This conference will take place immediately preceding CHI's Protein Kinase Targets (June 10-11, 2003)

More than 70% of the drugs on the market today are targeted to GPCRs, with sales of more than $30 billion. These targets will continue to be key in the search for effective therapeutics. This premier conference will address the important issues of GPCRs as targets and therapeutics and will present problem-solving strategies in the search for more effective GPCR-targeted drug discovery.

Corporate Sponsor: Corporate Support:

Scientific Advisor
Dr. John Van Drie, Vertex Pharmaceuticals Incorporated

Keynote Address
GPCRomics: Comprehensive Target Evaluation of a Protein Family
Dr. Marvin Bayne, Vice President, Discovery Technologies, Schering-Plough Corporation

Speakers
Dr . Julian Beesley, LifeSpan BioSciences, Inc.
Dr. Martin Beinborn, Tufts University
Dr. Scott D. Feighner , Merck & Co., Inc.
Dr. Joseph P. Brown, LifeSpan BioSciences, Inc.
Dr. Miguel Garcia-Guzman, Vertex Pharmaceuticals Incorporated
Dr. Annette Gilchrist, Northwestern University and cue BIOtech, Inc.
Dr. Andrew Howard, Merck & Co., Inc.
Dr. Enoch Huang, Pfizer Discovery Technology Center
Dr. Kenneth A. Jacobson, National Institute of Diabetes and Digestive and Kidney Diseases, NIH
Dr. Michael Kauffman, Predix Pharmaceuticals, Inc.
Dr. Kenneth Lundstrom, Bio-Xtal (Switzerland)
Dr. John Macor, Bristol-Myers Squibb Company
Dr. David F. Mark, Hoffmann-La Roche, Inc.
Dr. Scott Miller, Senior Gr oup Leader, Ar ray BioPhar ma, Inc.
Dr. Magda Morton, Johnson & Johnson Pharmaceutical Research & Development
Dr. Harvey Motulsky, University of California, San Diego and GraphPad Software, Inc.
Dr. David Rawn, ReceptorBase, Inc.
Dr. Matthias Steger, Axovan Ltd. (Switzerland)
Dr. Anil Tarachandani, Merck & Co., Inc.

Structure
GPCRomics: Comprehensive Target Evaluation of a Protein Family
Progress in Developing High-Throughput Tools for GPCR
Use of Constitutively Active GPCRs as Tools for Drug Discovery

Targets
Sequence Motifs for GPCR Orphan Classification
Localization and Expression of GPCRs in Human Normal and Diseased Tissues
Use of siRNA for Target Validation

Drug Discovery
Identification of Highly Selective Pharmaceutical Ligands of Receptors Aimed at Elucidation of Their Function(s): A Case Study
Modeling and Engineering of GPCRs: Purine Receptors
Integration of Conformational Analysis, Robust and Scalable Synthetic Chemistry, and Favorable Physiochemical Properties in the Design and Execution of GPCR-Biased Lead Generation Libraries
Redefining GPCR Drug Discovery: Identifying Small Molecules Targeting Receptor Action
Case Study: Simultaneous Blockage of Two GPCR Results in a Novel and Highly Efficacious Approach to Treating Hypertension
Cell Lines for Drug Discovery: Elevating Target-Protein Levels using Engineered Transcription Factors

Screening
GPCR-Tailored Pattern Recognition: Accelerating Drug Discovery
Miniaturized Cell-Based High-Throughput Screening of GPCRs Using b-Lactamase Technology High-Throughput Screening with Transfluor® Technology
Developing a High Throughput Screen with the Transfluor Technology
Developing a GPCR Assay for High Information Content Screening

Technology Spotlight
Integrated In Silico Computational and Classical Methods for GPCR Drug Discovery and Optimization

PROGRAM

Sunday, June 8

5:00-6:00pm Early Registration and Poster and Exhibit Set-up
 

Monday, June 9

8:00am Registration, Poster and Exhibit Viewing, and Light Continental Breakfast

 

Structure

9:00 Welcome by Session Chairperson
Dr. Kenneth Lundstrom, Bio-Xtal

9:10 KEYNOTE ADDRESS
GPCRomics: Comprehensive Target Evaluation of a Protein Family
Dr. Marvin Bayne, Vice President, Discovery Technologies, Schering-Plough Corporation
The GPCR family of proteins has traditionally provided the pharmaceutical industry with a rich source of targets for drug discovery. The recent sequencing of the human genome has led to the compilation of the complete catalog of human GPCRs. Current GPCR research focuses on (1) determining which members of this family represent opportunities for therapeutic intervention and (2) how to efficiently identify small molecule modulators of these targets for drug development. GPCRomics is defined as the application of a wide range of technologies to this research effort.

9:50 Progress in Developing High-Throughput Tools for GPCR Crystallography: The MePNet Approach
Dr. Kenneth Lundstrom
Rational drug design can substantially speed up and improve drug discovery. Although >60% of the drug targets today are membrane proteins, very few high-resolution structures are available, due to the difficulty in expression, purification, and crystallization of these proteins. MePNet is a global consortium focusing on innovative technologies from cDNA expression to crystallography. A high-throughput approach has been taken to overexpress 100 GPCR targets in three expression systems (E. coli, Pichia pastoris, and SFV) followed by refolding/solublization, purification, and crystallization.

10:20 Use of Constitutively Active GPCRs as Tools for Drug Discovery
Dr. Martin Beinborn, Assistant Professor of Medicine, NEMC, Tufts University
In contrast to many wild type GPCRs, constitutively active mutants trigger ligand-independent signaling. At the same time, such mutant receptors are distinguished from corresponding wild type isoforms by systematically enhancing ligand efficacies. Taking advantage of this amplification, we have utilized constitutively active mutants as a magnifying glass to detect intrinsic activity of non-peptide ligands for GPCRs where the identification of agonist drugs has been difficult, e.g. peptide hormone receptors. Our success with receptors from both class A (cholecystokinin/gastrin) and class B (glucagon-like peptide-1) suggests that this approach to drug discovery is broadly applicable.

10:50 Poster and Exhibit Viewing, Refreshment Break

 

Targets

11:20 Sequence Motifs for GPCR Orphan Classification
Dr. Enoch Huang, Assistant Director and Department Head, Molecular Informatics, Pfizer Discovery Technology Center
An approach to discovering sequence patterns characteristic of ligand classes is described and applied to aminergic G protein-coupled receptors (GPCRs). Putative ligand-binding residue positions were inferred from considering three lines of evidence: conservation in the subfamily absent or underrepresented in the superfamily, any available mutation data, and the physicochemical properties of the ligand. A minimally defined motif discovered in this fashion is an appropriate computational tool for identifying additional, potentially novel aminergic GPCRs from a set of experimentally uncharacterized "orphan" GPCRs, complementing existing sequence matching, clustering, and machine-learning techniques.

11:50 Molecular Pathology of GPCRs: The Localization and Expression of G-Protein Coupled Receptors in Human Normal and Diseased Tissues
Dr . Julian Beesley, Director of European Sales, LifeSpan BioSciences, Inc.
The human genome project has provided a comprehensive source from which to mine the list of GPCRs, but their sequences provide almost no information about which genes are potential new drug targets. Over the past three years, LifeSpan has generated antibodies to 320 non-olfactory GPCRs and has built a database to identify those that are upregulated in diseases such as cancer, cardiovascular disease, Alzheimer's and Parkinson's diseases, stroke, diabetes, and inflammatory and respiratory diseases. In addition, these GPCRs have been localized across 25 human normal tissues and 10 brain regions to provide information about potential toxicity in the event that the protein is targeted for therapeutic intervention. Results from this comprehensive human protein localization atlas will be presented, including analysis of patterns of expression for this important group of proteins.

12:20 Use of siRNA for Target Validation
Dr. David Rawn, Senior Scientist, ReceptorBase, Inc.
ReceptorBase's MapRNAi technology quickly tests the capacity of genes to participate in naturally RNAi occurring RNAi networks. MapRNAi networks for given genes can be used to identify molecular pathways. We will show data from yeast and C. elegans G-protein mediated pathways and correlations with genetic data and cell-cycle-dependent mRNA expression data.

12:50 Lunch (on your own)

 

Drug Discovery

2:00 Comments by Session Chairperson
Dr. Annette Gilchrist, Northwestern University; and cue BIOtech, Inc.

2:10 Identification of Highly Selective Pharmaceutical Ligands of Receptors Aimed at Elucidation of Their Function(s): A Case Study
Dr. Scott D. Feighner , Senior Resear ch Fellow, Obesity and Metabolic Resear ch, Merck & C o., Inc.
The key to harnessing the potential therapeutic benefits of GPCRs relies in our ability to identify highly selective pharmaceutical ligands of these receptors aimed at elucidation of their function(s). We have witnessed in a short time the pairing of a growing number of biologically-active molecules with their long-sought receptors, while simultaneous efforts in genomics have continued to provide even more orphan GPCRs that await closure through identification of their natural ligands. Discussion will focus on the challenge ahead with particular emphasis on the development of therapeutics for the treatment of obesity.

2:40 Modeling and Engineering of GPCRs: Purine Receptors
Dr. Kenneth A. Jacobson, Chief, Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH
Homology modeling based on a rhodopsin template has enhanced understanding of molecular recognition in the binding site and of activation of GPCRs. Based on these insights, the next phase is to engineer GPCRs, i.e. systematically to alter the sequence in order to produce desired functional effects. The neoceptor approach is based on use of molecular modeling to alter the recognition elements of a GPCR binding site, such that only synthetic, small molecular agonists that are selectively matched on the basis of molecular complementarity will activate the mutant receptor. The ligand recognition profile of neoceptors need not correspond to the profile of the parent, native receptor.

3:10 Integration of Conformational Analysis, Robust and Scalable Synthetic Chemistry, and Favorable Physiochemical Properties in the Design and Execution of GPCR-Biased Lead Generation Libraries
Dr. Scott Miller, Senior Gr oup Leader, Ar ray BioPhar ma, Inc.
The integration of conformational analysis, robust and scalable synthetic chemistry, and favorable physiochemical properties in the design and execution of a GPCR-biased lead generation libraries will be described. Emphasis will be placed on the design of unique, druglike lead molecules and pragmatic synthetic schemes that allow for rapid follow-up of active compounds.

3:40 Poster and Exhibit Viewing, Refreshment Break

4:10 Redefining GPCR Drug Discovery: Identifying Small Molecules Targeting Receptor Action
Dr. Annette Gilchrist
Many biologically active molecules convey their signals via receptors coupled to heterotrimeric G proteins. At Cue BIOtech, we focus on inhibiting receptor action rather than receptor activation. Using peptides that mimic the critical interface between GPCRs and G proteins, the company has defined the critical pathways for biochemical and physiological responses associated with important therapeutic targets. This proprietary platform has been employed to identify small molecules that can specifically alter a single signaling pathway.

4:40 Case Study: Simultaneous Blockage of Two GPCRs Results in a Novel and Highly Efficacious Approach to Treating Hypertension
Dr. John Macor, Executive Director, Chemistry, Bristol-Myers Squibb Company
Angiotensin and endothelin are two distinct peptides that mediate vasoconstriction and other adverse cardiovascular events. Blocking their effects on the GPCRs that they enervate (i.e., AT1 and ETA receptors, respectively) has been used as means of reducing blood pressure and potentially reducing end organ damage due to hypertension. We have discovered a series of small molecules, which function as dual action receptor antagonists (DARAs), that concomitantly block both AT1 and ETA receptors. We will discuss the rationale of this approach, along with relevant structure-activity relationships, as well as the pharmacological characterization of these novel anti-hypertensives.

5:10 Cell lines for Drug Discovery: Elevating Target-Protein Levels using Engineered Transcription Factors
Dr. Magda Morton, Johnson & Johnson Pharmaceutical Research & Development
Drug discovery requires high quality, high throughput bioassays for lead identification and optimization. These assays are usually based on immortalized cell-lines, which express the selected drug target either naturally or as a consequence of transfection with the cDNA encoding the target. Unfortunately, these systems have associated problems including patent restrictions, possible abnormalities in the processing of protein in transfected cell lines and low-level target expression in wild type cells. Here, the use of engineered transcription factors based on the Cys2-His2 zinc finger domain is demonstrated as a method to activate an endogenous gene of interest without the use of isolated or purified cDNA of the target gene. This approach generated a cell line that provided a high quality and pharmacologically validated, G-protein coupled receptor bioassay. In principle, this new technology is broadly applicable to any genes of therapeutic importance in any cell type.

5:40 Close of Day One

Tuesday, June 10

8:00am Poster and Exhibit Viewing and Light Continental Breakfast

 

Screening

8:30 Comments by Session Chairperson
Dr. Miguel Garcia-Guzman, Group Leader, Discovery Biology-Receptors, Vertex Pharmaceuticals Incorporated

8:40 GPCR-Tailored Pattern Recognition: Accelerating Drug Discovery
Dr. Matthias Steger, Head of Combinatorial Chemistry, Axovan, Ltd.
AXADDIS (Axovan's Computer Supported Accelerated Drug DIscovery System) is a GPCR-tailored, fully integrated, and versatile computational platform built on the amalgamation of broad GPCR knowledge. Consisting of proprietary databases and computational tools, AXADDIS has already been shown to have a considerable impact at various levels of the drug discovery process, e.g., by creating a GPCR-biased albeit diverse collection of druglike, small molecules and by improving and inspiring the hit-to-lead-to-clinical candidate optimization. Examples of AXADDIS applications (GPCR-bias of Axovan's library, pharmacophore recognition tools, scaffold hopping, etc.) will be presented.

9:10 Miniaturized Cell-Based High-Throughput Screening of GPCRs Using b-Lactamase Technology
Dr. Miguel Garcia-Guzman
We have developed transcriptional cell-based functional assays for GPCR using the b-Lactamase reporter gene and fluorescent probes. This assay format is both reliable and sensitive and can be miniaturized to run screens in high-density plates with 3456-wells. Different instruments have been developed that allow running ultrahigh-throughput screens for GPCRs in the lab. These instruments and assay technologies have been efficiently incorporated into our discovery platform. Examples of the application of this approach to identify selective GPCR ligands will be described.

9:40 Developing a High Throughput Screen with the Transfluor Technology
Dr. David F. Mark, Senior Research Director, Roche Discovery Technologies, Hoffmann-La Roche, Inc.
Norak Bioscience's Transfluor® technology provides a cell-based assay for high-throughput screening of known and orphan GPCRs based on the redistribution of barrestin-GFP. Quantitation using the Transfluor technology is accomplished on multiple image analysis platforms and discriminates agonists, partial agonists, and antagonists while providing valuable pharmacological information on ligand efficacy and potency. In contrast to present methods of screening GPCRs, the power of the Transfluor assay is in its simplicity, sensitivity, and applicability to all GPCRs without requiring prior knowledge of natural ligands or how a given receptor is coupled to downstream signaling pathways. (This new application has just recently been published.)

10:10 Poster and Exhibit Viewing, Refreshment Break

10:45 Developing a GPCR Assay for High Information Content Screening
Dr. Anil Tarachandani, Merck & Co., Inc.
Summary unavailable at time of printing.

Technology Spotlight

11:15 Integrated In Silico Computational and Classical Methods for GPCR Drug Discovery and Optimization
Dr. Michael Kauffman, President and CEO, Predix Pharmaceuticals, Inc.
Predix's drug discovery platform uses proprietary 3-dimensional modeling technology (PREDICT™) together with an integrated in silico screening platform (RISS™) to obtain novel 3D structures of GPCRs and novel drug candidates. In just the past 24 months, our platform has allowed us to obtain 3D structures for nearly 50 GPCRs covering 8 different families. This platform has successfully identified novel drug-like compounds that bind specifically to GPCR targets in affinity assays. Using these structures in our in silico screening processes, hit rates for novel drug candidates are 10-25%, compared to <0.1% with standard High Throughput Screening (hits are defined as compounds with <10µM experimentally determined binding affinity). Most of the computationally driven Predix hits have affinities of <1µM, typically 1-100nM. Predix has also utilized its unique ICELR-3D lead optimization algorithms to transform its leads into early development candidates. Our programs in NK1 and 5-HT1A have entered early animal testing, and we are targeting initial human clinical trials in early 2004.

11:35 Lunch (sponsorhips available) with Kinase Conference Attendees

1:00 Close of Conference


Sponsoring Publications:

Web Partner:  



Predix Pharmaceuticals integrates proprietary 3D structure determination, computational chemistry technologies, and classical medicinal chemistry, creating a drug discovery platform that dramatically accelerates the generation of new drug candidates associated with any GPCR whose ligand is known.


Sangamo BioSciences develops and markets novel transcription factors capable of regulating genes. The company s technology has been successfully used to activate mammalian GPCRs in a variety of cell lines. Cell lines over-expressing a particular GPCR can be created in this unique way, bypassing the need to license cDNA patents.


In addition to exhibiting, there are many sponsorship opportunities for your company to maximize its exposure and influence. They include conference-specific sponsorships, technology workshops, networking receptions, delegate bags, etc. We are also ready to work with you in customizing a solution to meet your specific marketing objectives. Make a lasting impression as a thought leader by taking advantage of these marketing tools. The early rate for exhibitors is April 18, 2003-register to exhibit by that date and you could save up to $350!

For sponsorship and exhibit information, please contact:
Angela Parsons at 781-972-5467; email: aparsons@healthtech.com

Hotel Information
Westin Copley Place Hotel
10 Huntington Avenue
Boston, MA 02116
T: 617-262-9600 o F: 617-424-7483
Room Rate: $199 S/D
Cut-off Date: May 20, 2003
Please call the hotel directly to make your room reservation. Identify yourself as a Cambridge Healthtech Institute conference attendee to receive the reduced room rate. Reservations made after the cut-off date or after the group room block has been filled (whichever comes first) will be accepted on a space-and-rate-availability basis. Rooms are limited, so please book early.

Travel Information
Special Airline Discounts Available
Special Zone and Discount Fares have been established for this conference with United Airlines. Please call United Airlines Meeting Reservation Desk at 800-521-4041 and reference ID#579YS.

Call for Posters
Cambridge Healthtech Institute encourages attendees to gain further exposure by presenting their work in the poster sessions. Please fill out the registration form, with the poster title and primary author. To ensure inclusion in the conference CD, a one-page abstract must be submitted and registration must be paid in full by March 9, 2003.   Click here for poster instructions


 

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