Model Organisms in Drug Discovery

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COXIBs 214 CPLA2 orthologs 216 Cre/lox 107 CSBP2 21 cyclin-dependent kinase (CDK) inhibitors 13, 156 cyclodiene 162 cycloheximide 97 cyclooxygenases 204, 212, 214–17, 227 cyclophilin 16 cyclosporin 265 cyclosporin A 14–16, 264 Cyp1 and Cyp2 16 cystic fibrosis 20 daf-2 65 DAPT 143 deletion collections 25–9 dementias 270 denaturing gradient HPLC 232–3 depression 45, 47–50, 54, 269 descriptors 63–4 Devgen 50, 52, 56, 57, 65, 66, 69, 70 Dfd 83 diabetes 45, 65, 132, 155, 203, 259–60 diazepam 205 Dicer 57 Dif 172 digoxin 155 dimethylsulfoxide tolerance 97 Diptercin 172 disease models 50, 51, 86 Dmp53 139 dMyc 125 DNA chips 58 DNA microarrays 24–5, 58, 175 dominant modifier screens 132 dominant mutation screens 238 L-dopa 143 dopamine antagonists 69, 71 Dorsal 172 double-stranded RNA (dsRNA) 57, 89, 90, 105, 139, 170 doxurubicin 143 drinking assay 52, 56, 66–7, 69, 71 Drk 125 Drosomycin 172, 173 Drosophila 4, 5–6, 81–117, 119–51, 254 analytical tools 105–8 automated fly sorting and dispensing 108–9 balancer chromosomes 102–3 BMS AG6B 163 cell culture 109 cell growth inhibition 144 INDEX 281 chemical genetics 98, 141–5 comparative genomics 82–5 compound screens 94–8 conservation 82–5, 119–27 Cre/lox 107 EP screens 132, 134 eye spot test 100 FLP/FRT 106–7 forward genetics 85–7, 128–37 Gal4/UAS system 96, 105–6 GAL80 107–8 gene mapping 135–7 genetic screens 162 genetic toxicity 98–101 genome 3 genome profiling 175 high-throughput technology 109–10 homeotic gene 83 information resources 101–2 innate immunity 172 insulin signaling 84, 126–7, 171 Kc cells 109 lead identification 141–5 limitations as model 84–5 mechanism of action studies 92–4, 144–5, 156–9, 162 modifier screens 86, 132, 134–5 mutagenesis 103–5, 128–30 pathway conservation 84, 119–27 pathway kit analysis 89 practical gene classification 90–1 random mutagenesis 103–4 Ras pathway 84, 124–6 recessive screens 130–2 reverse genetics 87–8, 138–41 RNAi technology 89–90, 139–41, 171–2 S2 cells 109, 171, 172–4 sex-linked recessive lethal (SLRL) assay 99, 100–1 somatic mutation and recombination tests (SMART) 99–100, 101 target identification and validation 85–92, 127–41 targeted gene disruption 138–9 targeted mutagenesis 104–5 transgenics 108 wing spot test 99–100 WNT pathway 84, 120, 122–4 DRR1 and DRR2 17 drug development 154–6 discovery 1–7, 42–5, 72–3 screening 192–3, 210–12 drugability 91–2 druggable genome screening 251–78
282 INDEX Dscam 171 dual-energy X-ray absorptiometry (DEXA) 260–1 Duchenne muscular dystrophy 45 Duk1 19 Dyclone 25 dyclonine 24–5, 175–6 E3 ubiquitin ligase 21 efficacy testing 225 eicosanoids 214 eIF-2a kinases 20 eIF-4E-dependent protein synthesis 17 electrophysiology 65–6 Eli Lilly 20 embryonic lethality/viability 271 embryonic stem cells 191 Enbrel 265 endocrinology 259–62 enhancer/suppressor screen 53 enhancer trap 128 EP elements 106, 128, 129 EP screens 132, 134 epiboly 217 epidermal growth factor (EGF) 53 epilepsy 143 Erg2 176 ERK 124 erythropoiesis 19 estrogen 143 ethylmethanesulfonate (EMS) 52, 103, 128, 129–30, 135–6 ethyl-nitrosurea (ENU) mutagenesis 188, 189, 228–35 Ets-type proteins 84 EuGene 102 Exelixis 57 expression profiling 24–5, 42, 58–9, 175–6 ey-FLP 135 eye spot test 100 farnesyl protein transferase 22, 158 farnesyl transferase inhibitors 44–5 fas 236 fat-free 208–10 fertility 127 first-pass filter kit 89 FK506 14, 15, 16–17, 264 FKB1 16 FKBP12 16, 17 flat-top 240 FLP/FRT 106–7 Flp recombinase 131 fluorescence-activated cell sorting (FACS) 265 fluorescent lipid biosensors 207–8 fluorescent markers 66–7 fluorescent proteins 194 fluoxetine 47, 54, 158 Flybase 102 formalin paw assay 268 forward genetics 85–7, 128–37, 195, 198, 224–5, 235–42 Fpr1 16, 17 FPR1 16 fpr1 16, 17 FRAP/mTOR 240 frizzled and frizzled 2 140 FRT 131 Fujisawa 15 fumagillin 158 function inference 19 functional assay 50, 52 functional observation battery 268 fundus photography 263 Fz 122, 140 Ga subunit 17, 18 Gb/Gg 17 G-protein-coupled receptors (GPCRs) 17–18, 154 gain-of-function (GOF) 88, 129, 132, 134 Gal4 drivers 106 Gal4/UAS system 96, 105–6 GAL80 107–8 galantamine 155 gamma-rays 188 gamma-secretase inhibitor 158, 163, 168–9 gastric ulcer 253 GCN2 20 gene expression profiling 24–5, 42, 58–9, 175–6 gene expression topomap 58–9 gene knock-downs 50, 105 gene knock-outs 57–8 gene mapping 55–6, 135–7 gene names 11–12 gene sequence conservation 83–4 gene switches 107 gene targeting 252 gene trapping 252 genetic screens 170–2, 251–3 C. elegans 52–3, 252 Drosophila 162 zebra fish 187–9, 252 genetic toxicity 98–101 Genetics Company Inc. 142, 144
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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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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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Page 293: 288 INDEX yeast (continued) functio
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