Model Organisms in Drug Discovery

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146 DROSOPHILA – A MODEL SYSTEM Figure 5.5 Effect of rapamycin and wortmannin on Drosophila development. Wild-type Drosophila were grown in the presence of 50 mM rapamycin (Rapa) 300 mM wortmannin (WM) or 5% DMSO as a control. Two days after eclosion, the weight of the flies was measured phenotype in conjunction with the available information of the MOA in humans will provide information on which biological pathway is inhibited by the drug. Testing different mutations in genes encoding pathway components for resistance or hypersensitivity to the drug may further narrow down the target or identify it directly. When the target cannot be identified through existing mutations, mutations that render the flies resistant to the drug can be selected. Some of these mutations will identify the gene target or a closely associated protein. This approach has been used successfully for the identification of insecticide targets such as Methoprene and Ivermectin (Ashok et al., 1998; Kane et al., 2000). 5.4 Outlook From all multicellular organisms, the unprecedented wealth of biological and genetic information makes Drosophila a very promising tool for target and lead discovery using classical and chemical genetics. The number of disease models in Drosophila increases rapidly. These include models for a variety of neurodegenerative diseases (Muqit and Feany, 2002), metabolic diseases such as type 2 diabetes and various cancers. The availability of genetically sensitized systems suitable for genetic and chemical screening offers a highly synergistic approach to target and lead discovery. Over the past 20 years, Drosophila research has revolutionized our understanding of developmental biology like no other organism. We are convinced that the next 20 years will see an equally strong impact of this small fly on pharmaceutical research. By delivering in vivo validated targets and leads rich in biological information
about their function in a multicellular organism, we expect these targets and leads to have a much higher success rate in the validation process in other animal models and in clinical trials. The success of companies built on these model systems, including Exelixis, Inc., Develogen, AG and The Genetics Company, Inc., indicate that this is not only the view of passionate fly geneticists but is also perceived like this in the pharmaceutical and economic industries. 5.5 Acknowledgments We thank S. Breuer, K. Nairz, S. Oldham, F. Rintelen, B. Schindelholz, H. Stocker and M. Vegh for discussions and E. Niederer and Greg Cole for expert technical help in setting up INVOSCREEN TM . 5.5 References REFERENCES 147 Adachi-Yamada, T., Nakamura, M., Irie, K., Tomoyasu, Y., Sano, Y., Mori, E., Goto, S., et al. (1999). p38 mitogen-activated protein kinase can be involved in transforming growth factor beta superfamily signal transduction in Drosophila wing morphogenesis. Mol. Cell. Biol. 19, 2322–2329. Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. T. and Saltiel, A. R. (1995). PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J. Biol. Chem. 270, 27489–27494. Arcaro, A. and Wymann, M. P. (1993). Wortmannin is a potent phosphatidylinositol 3kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem. J. 296, 297–301. Ashok, M., Turner, C. and Wilson, T. G. (1998). Insect juvenile hormone resistance gene homology with the bHLH-PAS family of transcriptional regulators. Proc. Natl. Acad. Sci. USA 95, 2761–2766. Berg, C. A. and Spradling, A. C. (1991). Studies on the rate and site-specificity of P-element transposition. Genetics 127, 515–524. Berger, J., Suzuki, T., Senti, K. A., Stubbs, J., Schaffner, G. and Dickson, B. J. (2001). Genetic mapping with SNP markers in Drosophila. Nat. Genet. 29, 475–481. Bienz, M. and Clevers, H. (2000). Linking colorectal cancer to Wnt signaling. Cell 103, 311–320. Boettner, B. and Van Aelst, L. (2002). The RASputin effect. Genes Dev. 16, 2033–2038. Bo¨hni, R., Riesgo-Escovar, J., Oldham, S., Brogiolo, W., Stocker, H., Andruss, B. F., Beckingham, K., et al. (1999). Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4. Cell 97, 865–875. Bos, J. L. (1989). ras Oncogenes in human cancer: a review. [Erratum appears in Cancer Res. 1990; 50, 1352.] Cancer Res. 49, 4682–4689. Brazil, D. P. and Hemmings, B. A. (2001). Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem. Sci. 26, 657–664.
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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 103 and 104: 94 DROSOPHILA AS A TOOL FOR DRUG DI
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
Page 137 and 138: TARGET IDENTIFICATION/TARGET VALIDA
Page 151 and 152: CHEMICAL GENETICS 143 acid identity
Page 153: 3. A hit identifies a biologically
Page 157 and 158: REFERENCES 149 Han, Z. S., Enslen,
Page 159 and 160: REFERENCES 151 Rintelen, F., Stocke
Page 161 and 162: 6 Mechanism of Action in Model Orga
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
Page 169 and 170: ELUCIDATING THE MECHANISM OF COMPOU
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
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Page 193 and 194: 186 GENETICS AND GENOMICS IN THE ZE
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198 GENETICS AND GENOMICS IN THE ZE
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200 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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