Model Organisms in Drug Discovery

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10 Saturation Screening of the Druggable Mammalian Genome Hector Beltrandelrio, Francis Kern, Thomas Lanthorn, Tamas Oravecz, James Piggott, David Powell, Ramiro Ramirez-Solis, Arthur T. Sands and Brian Zambrowicz Functional annotation of the mammalian genome has become an important goal in the post-genome era. Genetic studies in model organisms provide an excellent approach for understanding gene function. The development of technologies for massive parallel production and analysis of mouse mutants is making it possible to screen through mutations in all druggable genes to identify targets with high value for drug discovery. By carrying out genetic screens in a mammalian model system, it is possible to screen directly for changes in physiology relevant to human disease treatment. Here we describe our biological screening strategy being carried out on 1000 mouse gene knockouts per year. This screen is focused on discovering the targets for the next generation of therapeutic products in the areas of metabolism, endocrinology, immunology, neurology, cardiology, ophthalmology, reproductive biology and oncology. 10.1 Introduction Genetic screens can be used potentially to scan a genome for genes that play a role in any process of interest. Early genetic screens were carried out in invertebrate model organisms and included saturation screens of Drosophila Model Organisms in Drug Discovery. Edited by Pamela M. Carroll and Kevin Fitzgerald Copyright © 2003 John Wiley & Sons, Ltd. ISBN: 0-470-84893-6
252 SATURATION SCREENING OF DRUGGABLE MAMMALIAN GENOME to identify genes involved in organization of the body plan during development (Nusslein-Volhard and Wieschaus, 1980) and screens in Caenorhabditis elegans to identify genes involved in producing the invariant cell lineage pattern (Horvitz and Sulston, 1980; Chalfie et al., 1981; Hedgecock et al., 1983). These screens relied on saturation mutagenesis to interrogate the genome for the set of genes involved in these processes and led to the discovery of genes such as the homeobox genes and apoptosis regulators involved in development across all invertebrate and vertebrate species examined. Since these early screens, a tremendous number of additional genetic screens have been carried out in the fly and worm, further demonstrating the power of genetics for the dissection of pathways and processes. These screens require only a method for creating large numbers of tractable mutations in genes and a phenotype that can be measured. More recently, genetic screening has been adapted for the vertebrate model organisms of zebrafish and mice. In zebrafish, both chemical mutagenesis (Mullins et al., 1994; Haffter et al., 1996) and gene trapping (Golling et al., 2002) have been combined with phenotypic screens to identify mutations affecting development of the neural crest, pigmentation, jaw, branchial arches, visual system, heart and other internal organs, ear, retina, brain, midline, shape and movement (Brockerhoff et al., 1995; Abdelilah et al., 1996; Baier et al., 1996; Brand et al., 1996; Chen et al., 1996; Granato et al., 1996; Kelsh et al., 1996; Malicki et al., 1996a,b; Neuhauss et al., 1996; Odenthal et al., 1996; Piotrowski et al., 1996; Schier et al., 1996; Solnica-Krezel et al., 1996; Stemple et al., 1996). These screens take advantage of the large number of offspring, oviparous development and transparent nature of the zebrafish embryo that make it an excellent system for the study of vertebrate development. These studies undoubtedly will result in the identification of a large number of genes required for vertebrate development. For the purpose of drug discovery, effective genetic screens in mammals would allow one to dissect mammalian physiology to identify key genes with therapeutic relevance as potential drug targets. Some might consider genetic screens in mammals to be impossible logistically, but recent advances in mutagenesis and screening methods in mice are facilitating functional dissection of the mammalian genome. Advances in the scale and speed of gene targeting (Walke et al., 2001; Abuin et al., 2002) and the development of genome-wide gene trapping (Zambrowicz et al., 1998; Wiles et al., 2000; Leighton et al., 2001; Mitchell et al., 2001) in mouse embryonic stem cells have resulted in saturation of the mammalian genome with tractable mutations in large numbers of genes. This has been combined with the recent miniaturization of a broad array of medical technologies and the transfer of many disease challenge assays to the mouse model to enable detailed diagnostic analysis of mice. The mouse is a model organism that is ideal for studying many aspects of mammalian physiology with direct medical relevance. Screens are currently being used to identify genes involved in insulin
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Model Organisms in Drug Discovery M
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Copyright u 2003 John Wiley & Sons
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Contents List of contributors .....
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CONTENTS ix 7 Genetics and Genomics
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List of Contributors Hector Beltran
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LIST OF CONTRIBUTORS xiii Stefan Sc
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1 Introduction to Model Systems in
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Organism INTEGRATING MODEL ORGANISM
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INTEGRATING MODEL ORGANISM RESEARCH
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INTEGRATING MODEL ORGANISM RESEARCH
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10 GROWING YEAST FOR FUN AND PROFIT
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3 Caenorhabditis elegans Functional
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THE DRUG DISCOVERY PROCESS 43 thoug
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multivulva phenotype of Ras gain-of
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disease. These molecular targets ar
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FROM DISEASE TO TARGET 49 Figure 3.
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FROM DISEASE TO TARGET 51 Figure 3.
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signaling pathway. The third catego
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FROM DISEASE TO TARGET 55 resistant
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phenomenon was first observed in C.
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profiles. The C. elegans gene expre
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emerging technologies. Forward gene
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The compound library LEAD DISCOVERY
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LEAD DISCOVERY 65 previous section,
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LEAD DISCOVERY 67 Figure 3.5 Distri
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Compound learning set for assay val
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10 000-15 000 human drug targets ar
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transporter itself. The SSRIs that
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REFERENCES 75 de Montigny, C., Blie
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REFERENCES 77 Lewis, J. A., Wu, C.
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REFERENCES 79 Tissenbaum, H. A. and
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82 DROSOPHILA AS A TOOL FOR DRUG DI
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100 DROSOPHILA AS A TOOL FOR DRUG D
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5 Drosophila - a Model System for T
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EVOLUTIONARY CONSERVATION OF DISEAS
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TARGET IDENTIFICATION/TARGET VALIDA
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CHEMICAL GENETICS 143 acid identity
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3. A hit identifies a biologically
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about their function in a multicell
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REFERENCES 149 Han, Z. S., Enslen,
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REFERENCES 151 Rintelen, F., Stocke
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6 Mechanism of Action in Model Orga
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INTRODUCTION TO COMPOUND DEVELOPMEN
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MODEL ORGANISMS ARRIVE ON THE SCENE
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ELUCIDATING THE MECHANISM OF COMPOU
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ELUCIDATING THE MECHANISM OF COMPOU
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A CASE STUDY FOR ALZHEIMER’S DISE
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NEW CHEMICAL GENETIC STRATEGIES 171
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A CASE STUDY FOR INNATE IMMUNITY 17
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GLOBAL GENE EXPRESSION STUDIES IN M
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As described above, the extensive i
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REFERENCES 179 Austin, J. and Kimbl
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REFERENCES 181 Hughes, T. R., Marto
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REFERENCES 183 Sin, N., Meng, L., W
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186 GENETICS AND GENOMICS IN THE ZE
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Page 205 and 206: 198 GENETICS AND GENOMICS IN THE ZE
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Page 209 and 210: 8 Lipid Metabolism and Signaling in
Page 211 and 212: FISH AS A MODEL ORGANISM 205 genes
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Page 215 and 216: LIPID METABOLISM SCREEN 209 Figure
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Page 219 and 220: ZEBRAFISH AS A MODEL SYSTEM 213 Fig
Page 221 and 222: ZEBRAFISH AS A MODEL SYSTEM 215 Reg
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Page 229 and 230: 224 CHEMICAL MUTAGENESIS IN THE MOU
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Page 259 and 260: 254 SATURATION SCREENING OF DRUGGAB
Page 285 and 286: 280 INDEX bupropion 92 busulfan 143
Page 287 and 288: 282 INDEX Dscam 171 dual-energy X-r
Page 289 and 290: 284 INDEX L-685,818 16 lead discove
Page 291 and 292: 286 INDEX protein function 19-22 pr
Page 293: 288 INDEX yeast (continued) functio
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