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SUNDAY, APRIL 23

Pre-Conference Symposium
ENCODED COMPOUND LIBRARIES
Focusing on Encoded Small Molecule Library Synthesis
(Separate Registration Required)
Please visit www.healthtech.com/2006/ecl/index.asp for details.

MONDAY, APRIL 24

7:30am Conference Registration

ENHANCED SCREENING METHODS

8:30 Evolution and Overview
Chairperson: Vicki Nienaber, Ph.D., Senior Director, Lead Discovery, SGX Pharmaceuticals, Inc.

8:45 Accurate Docking Ligands and Fragments to a Flexible Receptor 
Ruben Abagyan, Ph.D., Professor, Department of Molecular Biology, The Scripps Research Institute
The main challenge of structure based ligand design is predicting the correct binding pose for ligands and fragments docked into a flexible receptor pocket. Including the receptor pocket flexibility into account in ligand docking, docking remains a task highly specific to the nature of the receptor. We formulated a docking protocol which is relatively general and includes both the side-chain sampling and loop movements. This protocol can be further enhanced and generalized if the backbone is sampled according to the relevant normal modes. The ICM docking protocol led to the discovery of novel inhibitors against a number of biomedical targets, including de novo discovery of antogonists of RAR and thyroid hormone receptor. discovery of inhibitors of alpha1-antityrpsin amyloid formation, discovery of new antimalarial agents. Predicting conformations of potentially flexible protein loops is an important task in docking ligands and fragments. We introduced an improved conformational sampling protocol that predicted loops of up to 15 residue long with high crystallographic resolution accuracy (under 0.5 for the backbone atoms and under 1A for the side chains). The protocol was tested on a large benchmark of loops. A technology for identification and evaluation of a druggable pocket, in particular at protein-protein interfaces, is also presented.

9:15 Adding Value to NMR-Based Fragment Screens by Using Competition Binding or Functional Assays
Brian Stockman, Ph.D., Associate Research Fellow, Exploratory Medicinal Sciences, Pfizer, Inc.
Fragment-screening by NMR methods typically yields a list of compounds that bind to the target of interest. These initial hits may or may not bind in the desired active site and may or may not possess inhibitory activity. Conducting the NMR screen using competition methods or by direct functional readout, however, results in a list of hits that bind at the desired active site and/or inhibit function. Importantly, the added value of these hits is obtained with higher throughput compared to direct binding methods.

9:45 Target Immobilized NMR Screening: Can the Fragment-Based Approach to Drug Discovery Be Applied to Membrane Proteins?
Gregg Siegal, Ph.D., Chief Scientific Officer, ZoBio BV
Fragment-based drug discovery (FBDD) is gaining increased attention because it generates “lead like” compounds and has been successfully applied to challenging targets such as protein-protein interactions. However, FBDD is generally only applicable to soluble proteins available in large quantities (10’s mg). TINS, target immobilized NMR screening, is a method that in principle, is applicable to insoluble integral membrane protein targets obtained in limited quantities. In TINS, the target is immobilized on a solid support. The mixture of compounds to be tested for binding is pumped over the support and binding is detected by 1D 1H NMR spectroscopy of the ligands. Binding to the immobilized target results in a simple reduction in peak amplitude, which is conveniently detected by comparison with a control sample. More than 2,000 compounds can be applied to a single sample of the target with no effect on ligand binding, thereby opening the way to screening an entire fragment library using a single sample of the target. Specialized hardware has been developed to enable TINS as a flow-injection medium-throughput screening system. Using this hardware and an optimized fragment library, screening can be carried out in an automated manner using less than 5 mg of the target. TINS has been successfully applied to a growing number of soluble proteins and nucleic acids. Presented will be the latest results using the instrument, including initial attempts to apply TINS to bacterial membrane proteins and G-protein coupled receptors.

10:45 Crystallography-Driven Fragment-Based Lead Generation for Oncology Targets
Vicki Nienaber, Ph.D., Senior Director, Lead Discovery, SGX Pharmaceuticals, Inc.
Crystallographic screening has proven to be a valuable asset in the field of fragment-based lead discovery. The technique has been successful as a stand-alone methodology and as a complement to other methods of hit detection such as NMR, computational docking and mass spectrometry. When used in conjunction with a high-throughput parallel structural biology platform including a dedicated synchrotron beamline, crystallographic screening as a stand-alone method can yield multiple high-quality starting points for drug discovery and provide key structural information that can facilitate rapid elaboration of the fragment hits into a lead series. Furthermore, the capability to pursue multiple targets in parallel enables a strategy that leads to the natural evolution of multiple high quality starting points for lead optimization and pre-clinical studies. Ultimately, a highly valuable drug discovery pipeline is the outcome. At SGX, this parallel lead discovery approach has been applied to a series of oncology targets. Results illustrating the power of crystallographic screening and parallel lead discovery to provide high quality leads for optimization will be presented.

11:15 X-Ray and Biophysical Methods to Drive Fragment-Based Lead Generation
Michael Hennig, Ph.D., Vice Director, Section Head, Molecular Structure Research, F. Hoffmann-La Roche Ltd.
Case examples for the application of fragment screening will be presented in order to illustrate the Roche process for this promising route for hit and lead generation. There will be an emphasis on the interplay of biophysical, X-ray crystallography and computational chemistry methods to facilitate the discovery of novel and differentiating chemical entities.

11:45 In Silico Fragment-Based Design
James H. Wikel, M.S., Chief Technology Officer, Coalesix, Inc.
An effective in silico method was used to identify fragments in the presence of a core scaffold. Multicriteria optimization and Interactive Evolutionary Computing (IEC) were combined to search a predefined chemistry space. A case study on antibacterial quinolone carboxylic acids represented by Cipro for the therapeutic treatment of tuberculosis will be presented. IEC searched a virtual chemistry space of 430,000 structures representing 5 positions as fragment attachment sites. Insights into the most appropriate fragment(s) at each position were determined.

1:15 Session Break

LOW AFFINITY BINDING FRAGMENTS
INTO POTENT LEADS: 
CHARACTERIZATION AND OPTIMIZATION

1:30 Puzzling Approaches to Drug Discovery
Chairperson: Maurizio Pellecchia, Ph.D., Associate Professor, Medicinal Chemistry & Structural Biology, Burnham Institute for Medical Research

1:40 NMR Auxiliary Binding Screen for Lead Optimization: Renin Inhibitor Example 
S. Donald Emerson, Ph.D., Research Fellow, Chemistry Technologies, Pfizer Inc. 

4:05 Fragment-Based Lead Discovery: Targeting Adaptive Sites and Allosteric Pockets
Stig K. Hansen, Ph.D., Senior Scientist, Department of Biology, Sunesis Pharmaceuticals
Protein kinases and phosphatases are key players in regulating signaling pathways implicated in the pathogenesis of a broad range of indications. However, the identification of specific and efficacious small molecule inhibitors of kinases and phosphatases remains a significant challenge. Fragment-based discovery methods are becoming increasingly important as starting points for drug discovery and can be a powerful approach for identifying novel leads. At Sunesis Pharmaceuticals we have used our fragment-based lead discovery approach, called Tethering®, to discover novel and potent inhibitors of a number of clinically relevant targets. In particular, Tethering® has been a powerful tool in targeting adaptive and allosteric sites, whose small molecule binding interfaces may be impossible to predict from static crystal structures. Data on the application of Tethering® to kinases and phosphatases will be presented.

5:30 Networking Cocktail Reception

TUESDAY, APRIL 25

8:45am Approaching the Final Frontiers
Chairperson: Jane Withka, Ph.D., Associate Research Fellow, Pfizer Inc.

8:55 Fragment-Based Discovery of a Potent Inhibitor of the Antiapoptotic Protein Bcl-xL
Andrew M. Petros, Ph.D., Associate Research Fellow, Department of Structural Biology, Abbott Laboratories
A potent inhibitor of the antiapoptotic protein Bcl-xL was discovered thru a combination of fragment-based screening and parallel synthesis. An initial NMR-based screen yielded a biaryl acid with an affinity (Kd) of ~ 300 µM for the protein. Following the classical “SAR by NMR” approach, a second site ligand was identified which bound close to the first site biaryl acid. Parallel synthesis, guided by NMR-based structural studies, yielded a ligand with an affinity (Ki) for Bcl-xL of ~ 36 nM. This work provides a paradigm for fragment-based discovery of molecules aimed at disrupting protein-protein interactions.

9:25 From Fragment Hit to Clinical Trials ­ A Case History
Robin A.E. Carr, Ph.D., Vice President, Drug Discovery, Astex Therapeutic
A fragment hit to clinical trails case history will be presented. Astex has used high-throughput X-ray crystallography(Astex’s PyramidTM technology) to identify high efficiency binding molecular fragments that bind to an oncology kinase target. Structure-based optimization of a fragment hit, using protein-ligand X-ray structures of synthesized molecules, allowed the rapid identification of compounds with potent kinase and anti-proliferative activity and impressive activity in xenograft studies. One of these compounds has been taken through pre-clinical development into clinical trials. Of interest, is the process by which this fragment was progressed into a lead and then on to clinical trials.

9:55 Networking Refreshment Break, Poster and Exhibit Viewing

10:25 Fragment-Based Discovery of Novel Inhibitors for Gleevec-Resistant BCR-Abl 
Stephen K. Burley, M.D., D.Phil., Chief Scientific Officer, SGX Pharmaceuticals, Inc.
SGX Pharmaceuticals, Inc. has developed a fragment-based drug discovery platform that utilizes high-throughput X-ray crystallography for lead identification/optimization. The proprietary FAST™ (Fragments of Active Structures) process exploits crystallographic screening to detect, visualize, and identify small ligands (MW 150-200) that are bound to the target protein. Each member of the FAST™ fragment/scaffold library was selected to be amenable to rapid chemical elaboration at two or three points of chemical diversity using parallel organic synthesis. Initial lead optimization involves using our knowledge of the co-crystal structure of the target-fragment complex and advanced computational chemistry tools to guide synthesis of small focused linear (one-dimensional) libraries. These linearly elaborated fragments/scaffolds are then evaluated with in vitro biochemical and cellular assays and co-crystal structure determinations. Thereafter, optimal variations at each point of chemical diversity are combined to synthesize focused combinatorial (two- or three-dimensional) libraries that are again examined with assays and crystallography. (The potential chemical diversity of the fully elaborated FAST™ fragment/scaffold library far exceeds 160 million compounds.) Active compound series are prioritized for further medicinal chemistry and compound development efforts using the results of in vitro and in vivo ADME and in vitro toxicology studies. Successful applications of the FAST™ fragment-based lead discovery/optimization process will be presented for a portfolio of well-validated oncology targets, including wild-type and Gleevec-resistant BCR-ABL.

10:55 Apoptosis Based Therapies: A Fragment- and Structure-Based Approach
Maurizio Pellecchia, Ph.D., Associate Professor, Medicinal Chemistry & Structural Biology, Burnham Institute for Medical Research
We have recently reported on an NMR-based approach, named SAR by ILOEs (structure activity relationships by interligand nuclear Overhauser effect), that makes use of protein mediated ligand-ligand ILOEs in complex mixtures, molecular modeling, and synthetic chemistry to identify initial weak hits and convert them into bi-dentate compounds with higher affinity. Combined with functional studies using the resulting ligands, the SAR by ILOEs method represents an ideal approach to reverse chemical-genetics and drug discovery. I will report on our recent applications on the design and synthesis of compounds that block or promote apoptosis.

12:00pm Close of Conference

Scientific Advisory Board

• Roderick Hubbard, Ph.D., Senior Fellow, the Vernalis Group of Companies and
   University of York
• Jeffrey R. Huth, Ph.D., Senior Investigator, Structural Biology, Abbott
   Laboratories
• Wolfgang Jahnke, Ph.D., Leading Scientist, Discovery Technologies, Novartis
• Ellen Laird, Ph.D., Senior Research Investigator, Array BioPharma
• Tudor I. Oprea, M.D., Ph.D., Professor and Chief, Division of Biocomputing, Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine

Conference Image Courtesy of Astex Therapeutics. The image is an X-ray crystal structure of 6-methylaminopyrazine- 2-carbothioic acid amide bound into the active site of cyclin dependent kinase 2 (CDK2) . The ligand is shown colored by atom type and CDK2 as a surface colored by electrostatic potential (blue +ve and red -ve charge)