Model Organisms in Drug Discovery

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76 C. ELEGANS FUNCTIONAL GENOMICS IN DRUG DISCOVERY Holsboer, F. (1999). The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J. Psychiatr. Res. 33, 181–214. Horrobin, D. F. (2001). Realism in drug discovery – could Cassandra be right? Nat. Biotechnol. 19, 1099–1100. Hosono, R. and Kamiya, Y. (1991). Additional genes which result in an elevation of acetylcholine levels by mutations in Caenorhabditis elegans. Neurosci. Lett. 128, 243–244. Hosono, R., Hekimi, S., Kamiya, Y., Sassa, T., Murakami, S., Nishiwaki, K., Miwa, J., et al. (1992). The unc-18 gene encodes a novel protein affecting the kinetics of acetylcholine metabolism in the nematode Caenorhabditis elegans. J. Neurochem. 58, 1517–1525. Jakubowski, J. and Kornfeld, K. (1999). A local, high-density, single-nucleotide polymorphism map used to clone Caenorhabditis elegans cdf-1. Genetics 153, 743–752. Jansen, G., Hazendonk, E., Thijssen, K. L. and Plasterk, R. H. (1997). Reverse genetics by chemical mutagenesis in Caenorhabditis elegans. Nat. Genet. 17, 119–121. Jazwinska, E. C. (2001). Exploiting human genetic variation in drug discovery and development. Drug Discov. Today 6, 198–205. Jiang, M., Ryu, J., Kiraly, M., Duke, K., Reinke, V. and Kim, S. K. (2001). Genome-wide analysis of developmental and sex-regulated gene expression profiles in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 98, 218–223. Kamath, R. S., Martinez-Campos, M., Zipperlen, P., Fraser, A. G. and Ahringer, J. (2001). Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol. 2, RESEARCH0002. Karp, J. E., Kaufmann, S. H., Adjei, A. A., Lancet, J. E., Wright, J. J. and End, D. W. (2001). Current status of clinical trials of farnesyltransferase inhibitors. Curr. Opin. Oncol. 13, 470–476. Kaufmann, S. H. and Hengartner, M. O. (2001). Programmed cell death: alive and well in the new millennium. Trends Cell Biol. 11, 526–534. Kim, J., Poole, D. S., Waggoner, L. E., Kempf, A., Ramirez, D. S., Treschow, P. A. and Schafer, W. R. (2001a). Genes affecting the activity of nicotinic receptors involved in Caenorhabditis elegans egg-laying behavior. Genetics 157, 1599–1610. Kim, S. K., Lund, J., Kiraly, M., Duke, K., Jiang, M., Stuart, J. M., Eizinger, A., et al. (2001b). A gene expression map for Caenorhabditis elegans. Science 293, 2087–2092. Kimura, K. D., Tissenbaum, H. A., Liu, Y. and Ruvkun, G. (1997). daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans [see comments]. Science 277, 942–946. Kuwabara, P. E. and O’Neil, N. (2001). The use of functional genomics in C. elegans for studying human development and disease. J. Inherit. Metab. Dis. 24, 127–138. Kwok, P. Y. (2001). Methods for genotyping single nucleotide polymorphisms. Annu. Rev. Genomics Hum. Genet. 2, 235–258. Lahana, R. (1999). How many leads from HTS? Drug Discov. Today 4, 447–448. Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., Devon, K., et al. (2001). Initial sequencing and analysis of the human genome. Nature 409, 860– 921. Larsen, P. L. and Clarke, C. F. (2002). Extension of life-span in Caenorhabditis elegans by a diet lacking coenzyme Q. Science 295, 120–123. Lepine, J. P., Gastpar, M., Mendlewicz, J. and Tylee, A. (1997). Depression in the community: the first pan-European study DEPRES (Depression Research in European Society). Int. Clin. Psychopharmacol. 12, 19–29. Levitan, D., Doyle, T. G., Brousseau, D., Lee, M. K., Thinakaran, G., Slunt, H. H., Sisodia, S. S., et al. (1996). Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 93, 14940–14944.
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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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Page 35 and 36: 24 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
Page 59 and 60: FROM DISEASE TO TARGET 49 Figure 3.
Page 61 and 62: FROM DISEASE TO TARGET 51 Figure 3.
Page 63 and 64: signaling pathway. The third catego
Page 65 and 66: FROM DISEASE TO TARGET 55 resistant
Page 67 and 68: phenomenon was first observed in C.
Page 69 and 70: profiles. The C. elegans gene expre
Page 71 and 72: emerging technologies. Forward gene
Page 73 and 74: The compound library LEAD DISCOVERY
Page 75 and 76: LEAD DISCOVERY 65 previous section,
Page 77 and 78: LEAD DISCOVERY 67 Figure 3.5 Distri
Page 79 and 80: Compound learning set for assay val
Page 81 and 82: 10 000-15 000 human drug targets ar
Page 83 and 84: transporter itself. The SSRIs that
Page 85: REFERENCES 75 de Montigny, C., Blie
Page 89 and 90: REFERENCES 79 Tissenbaum, H. A. and
Page 91 and 92: 82 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
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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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