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Encoded chemistry allows for the creation of large combinatorial small molecule drug libraries by encoding each
compound with a tag. Significant expansion of library size to over 1 billion compounds has recently been made possible
by targeting each compound at the molecular level with DNA. Older combinatorial encoded approaches like aptamers
have born their first fruit with the approval of the Macugen Aptamer for macular degeneration. Join this exciting
symposium to see what the latest efforts are at exploiting larger libraries with advanced screening methods to identify
tomorrow’s blockbuster compounds. |
1:00pm Symposium Registration
2:00 Chairperson’s Introductory Comments
Barry A. Morgan, Ph.D., Vice President, Chemistry, Praecis Pharmaceuticals
| 2:05 DirectSelect Technology: Validation of Creating and Screening Billion Compound Libraries
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Barry A. Morgan, Ph.D.
We have developed a drug discovery technology, termed DirectSelect, which allows for the rapid production and screening of libraries consisting of billions of small molecules attached to a DNA tagging system. Using
combina-
torial chemistry methodologies optimized for DirectSelect, we have generated libraries containing over 5 billion compounds containing multiple scaffolds populated with thousands of synthon structures. The libraries were designed with a focus on creating “drug-like” molecules in uncharted chemical space. In this presentation, we will review how DirectSelect libraries are designed and assembled, and illustrate the remarkable speed and reproducibility of the screening method and the power of the technology to identify multiple families of inhibitors to macromolecular targets of therapeutic value. The vision for the technology is to continue to expand the libraries so that lead molecules can be directly selected for even the most difficult targets. |
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2:35 The Value of an Encoded Compound Collection: The Use of Statistical Methods in Library Design and HTS Data Interpretation
Doug W. Hobbs, Ph.D., Executive Director of Chemistry, Pharmacopeia Drug Discovery Inc.
Since the ability to encode combinatorial libraries has remained in the hands of a few organizations, there are many misunderstandings regarding the value of such a process. This talk will point out some advantages of encoding and demonstrate those advantages with specific examples.
3:05 From Tight Binders to Functionally Active Drug Leads: Discovery and Optimization of Hematide™, a Synthetic PEGylated Peptide for the Treatment of Anemia
Dr. Ashok Bhandari, Associate Director, Chemistry, Affymax, Inc.
Using phage display, we have discovered numerous peptides that exhibited tight binding to the EPO receptor. These peptides were able to be converted into stable, potent erythropoietic stimulating agents
(ESAs) after extensive sequence and architectural modifications. In addition, PEGylation of the peptides has resulted in a long acting agent named Hematide being tested in patients for the monthly administration for correction of anemia associated with chronic kidney disease (CKD). A summary of some of these modifications and clinical results obtained to date will be presented.
3:35 Refreshment Break
3:45 DNA-Programmed Assembly and Selection of Small Molecule Libraries
Jim Coull, Ph.D., Vice President, Technology Development & Commercialization, Ensemble Discovery Corporation
We have developed an integrated discovery platform for synthesis and identification of compounds with desired functional properties. Synthetic oligonucleotide templates are used to program the stepwise combinatorial assembly of diverse, complex, small molecule libraries in a single pot. After each reaction step, products are purified to remove excess reactants and side products. Following assembly, each compound remains attached to the unique DNA strand which programmed its synthesis. An ultra small-scale solution-phase binding assay is then used to select the library for compounds having desired binding properties. High- throughput hybridization and sequencing allows the entire population of binders (weak to strong) to be analyzed. Thus, SAR information is provided in every selection experiment. Based upon selection results and the modularity of the chemical synthesis method, follow-on libraries can be rapidly generated and selected to improve compound properties. This integrated synthesis and selection platform incorporates a number of novel features not found in previous DNA encoding approaches. A description of the system with results from the synthesis and selection of drug-like compounds will be presented.
| 4:15 KEYNOTE SPEAKER
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From Bacteriophage T4 to Macular Degeneration in 15 Years
Larry M. Gold, Ph.D., Chief Executive Officer and Chairman of the Board, SomaLogic, Inc.
Methods for identifying aptamers were discovered in the late 1980's, and pub-
lished in late 1990 by Tuerk, Gold, Ellington, and Szostak. The work that led to aptamers as a drug discovery platform, as well as the first such drug (Macugen, for the treatment of macular degeneration), will be described in gory detail. The understandable desire for typing as a substitute for biochemistry-based discovery will be chastized as the major error made by most oligonucleotide companies before NeXstar. A useful interface between aptamers and drugs derived from "encoded compound libraries" (or other small molecule discovery programs) will be proposed for the near-term future. |
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| 4:45 DISCUSSION WITH SPEAKERS |
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Is Larger Better: Which Approach to Building and Mining Compound Libraries Will Deliver Results? |
5:30 Close of Symposium
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