Model Organisms in Drug Discovery

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152 DROSOPHILA – A MODEL SYSTEM Wassarman, D. A., Therrien, M. and Rubin, G. M. (1995). The Ras signaling pathway in Drosophila. Curr. Opin. Genet. Dev. 5, 44–50. Weinkove, D., Neufeld, T., Twardzik, T., Waterfield, M. and Leevers, S. (1999). Regulation of imaginal disc cell size, cell number and organ size by Drosophila class IA phosphoinositide 3-kinase and its adaptor. Curr. Biol. 9, 1019–1029. White, M. A., Nicolette, C., Minden, A., Polverino, A., Van Aelst, L., Karin, M. and Wigler, M. H. (1995). Multiple Ras functions can contribute to mammalian cell transformation. Cell 80, 533–541. Xu, T. and Rubin, G. M. (1993). Analysis of genetic mosaics in developing and adult Drosophila tissues. Development 117, 1223–1237. Yenush, L. and White, M. F. (1997). The IRS-signalling system during insulin and cytokine action. Bioessays 19, 491–500. Zhang, H., Stallock, J. P., Ng, J. C., Reinhard, C. and Neufeld, T. P. (2000). Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes Dev. 14, 2712–2724. Zimmermann, S. and Moelling, K. (1999). Phosphorylation and regulation of Raf by Akt (protein kinase B). Science 286, 1741–1744.
6 Mechanism of Action in Model Organisms: Interfacing Chemistry, Genetics and Genomics Pamela M. Carroll, Kevin Fitzgerald and Rachel Kindt Each year pharmaceutical companies lose billions of dollars on compounds that fall out of development due in part to an unknown mechanism of action. In addition, better versions of compounds that are currently on the market are, in some cases, not being pursued because the mechanism by which the compound functions is unclear. The ability of small molecules with known mechanisms of action to affect Caenorhabditis elegans and Drosophila through their therapeutically relevant targets demonstrates that these same systems might have utility in the identification of molecular targets for compounds with unknown mechanisms. Advances in Drosophila and C. elegans research allow the combination of genome sequence information, gene expression profiles and genome-wide mutations to be used in an unprecedented dissection of a complex organism. This chapter will focus on the technical and innovative advantages of model organisms in discovering compound mechanism of action, as well as providing detailed accounts of compound utility in simple organism ‘disease models’. Model Organisms in Drug Discovery. Edited by Pamela M. Carroll and Kevin Fitzgerald Copyright © 2003 John Wiley & Sons, Ltd. ISBN: 0-470-84893-6
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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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Page 109 and 110: 100 DROSOPHILA AS A TOOL FOR DRUG D
Page 127 and 128: 5 Drosophila - a Model System for T
Page 129 and 130: EVOLUTIONARY CONSERVATION OF DISEAS
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Page 151 and 152: CHEMICAL GENETICS 143 acid identity
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Page 155 and 156: about their function in a multicell
Page 157 and 158: REFERENCES 149 Han, Z. S., Enslen,
Page 159: REFERENCES 151 Rintelen, F., Stocke
Page 163 and 164: INTRODUCTION TO COMPOUND DEVELOPMEN
Page 165 and 166: MODEL ORGANISMS ARRIVE ON THE SCENE
Page 167 and 168: ELUCIDATING THE MECHANISM OF COMPOU
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Page 171 and 172: A CASE STUDY FOR ALZHEIMER’S DISE
Page 179 and 180: NEW CHEMICAL GENETIC STRATEGIES 171
Page 181 and 182: A CASE STUDY FOR INNATE IMMUNITY 17
Page 183 and 184: GLOBAL GENE EXPRESSION STUDIES IN M
Page 185 and 186: As described above, the extensive i
Page 187 and 188: REFERENCES 179 Austin, J. and Kimbl
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Page 193 and 194: 186 GENETICS AND GENOMICS IN THE ZE
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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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