Model Organisms in Drug Discovery

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x CONTENTS 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 . . 251 10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 10.2 Saturating the druggable genome. . . . . . . . . . . . . . . . . . . . 253 10.3 Screening the genome effectively for novel drug targets . . . 255 10.4 High-throughput biology: maximizing return from reverse genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 10.5 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 10.6 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 Index. ................................................ 279
List of Contributors Hector Beltrandelrio Lexicon Genetics Incorporated, 8800 Technology Forest Place, The Woodlands, TX 77381, USA Thierry Bogaert Devgen NV, Technologiepark 9, B-9052 Ghent-Zwijnaarde, Belgium Lynn Butler Devgen NV, Technologiepark 9, B-9052, Ghent-Zwijnaarde, Belgium Pamela M. Carroll Department of Applied Genomics, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543, USA Neil Dear Ingenium Pharmaceuticals AG, Fraunhoferstrasse 13, D-82152 Martinsried, Germany Steven A. Farber Department of Microbiology & Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA Kevin Fitzgerald Department of Applied Genomics, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543, USA Barbara Froesch The Genetics Company, Inc., Wagistrasse 27, CH-8952 Zu¨rich-Schlieren, Switzerland Dan Garza Department of Functional Genomics, Novartis Pharmaceuticals Corporation, 556 Morrive Avenue, SEF2026, Summit, NJ 07901, USA Johannes Grosse Ingenium Pharmaceuticals AG, Fraunhoferstrasse 13, D- 82152 Martinsried, Germany Ernst Hafen The Genetics Company, Inc., Wagistrasse 27, CH-8952 Zu¨rich- Schlieren, Switzerland Shiu-Ying Ho Department of Microbiology & Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA Model Organisms in Drug Discovery. Edited by Pamela M. Carroll and Kevin Fitzgerald. & 2003 John Wiley & Sons, Ltd. ISBN 0 470 84893 6
Page 1 and 2: Model Organisms in Drug Discovery M
Page 3 and 4: Copyright u 2003 John Wiley & Sons
Page 5 and 6: Contents List of contributors .....
Page 7: CONTENTS ix 7 Genetics and Genomics
Page 11 and 12: LIST OF CONTRIBUTORS xiii Stefan Sc
Page 13 and 14: 1 Introduction to Model Systems in
Page 15 and 16: Organism INTEGRATING MODEL ORGANISM
Page 17 and 18: INTEGRATING MODEL ORGANISM RESEARCH
Page 19 and 20: INTEGRATING MODEL ORGANISM RESEARCH
Page 21 and 22: 10 GROWING YEAST FOR FUN AND PROFIT
Page 51 and 52: 3 Caenorhabditis elegans Functional
Page 53 and 54: THE DRUG DISCOVERY PROCESS 43 thoug
Page 55 and 56: multivulva phenotype of Ras gain-of
Page 57 and 58: 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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8 Lipid Metabolism and Signaling in
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FISH AS A MODEL ORGANISM 205 genes
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LIPID METABOLISM SCREEN 207 transpo
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LIPID METABOLISM SCREEN 209 Figure
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the embryo media containing radioac
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ZEBRAFISH AS A MODEL SYSTEM 213 Fig
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ZEBRAFISH AS A MODEL SYSTEM 215 Reg
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aspirin, which has potent inhibitor
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REFERENCES 219 Chau, I. and Cunning
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REFERENCES 221 Patrono, C., Patrign
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224 CHEMICAL MUTAGENESIS IN THE MOU
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252 SATURATION SCREENING OF DRUGGAB
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280 INDEX bupropion 92 busulfan 143
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282 INDEX Dscam 171 dual-energy X-r
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284 INDEX L-685,818 16 lead discove
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286 INDEX protein function 19-22 pr
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288 INDEX yeast (continued) functio
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