Model Organisms in Drug Discovery

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Northwestern University 237 Notch signaling 143, 163–70 Notch1B genes 216 Novartis 13, 14–15, 18, 22 nrf-6 54 NS-398 216 nuclear factor kappa B (NF-kB) 172, 173–4 nutrient availability 127 Oak Ridge National Laboratory 237 obesity 236, 260–1 ‘off-target’ activity 156 olomoucine 158 OMIM database 50 oncology 271–2 open brain 240 open field test 267 open reading frames names 11 sequence tags (OSTs) 60 opioid receptors 268 opium 155 orotidine-5 0 -phosphate decarboxylase 22 orphan druggable genes 233–5 Ortho-McNeil 25 osteoporosis 253–4, 261–2 osteoprotegerin genes 253 ovalbumin challenge 265–6 overexpression analysis 29 oxotremorine 158 P element mutagenesis 103, 128, 129, 188–9 P element vectors 108 p38 kinase inhibitor 143 p38a kinase 21–2 p53 192–3 p53 139 pancreatic eukaryotic kinase (PEK) 20 pangolin/TCF 122, 123 parallel repository 231–2 Parkinson’s disease 143, 270 parthenolide 155, 173–4 patch-clamping 65–6 pathway conservation 43, 44–5, 84, 119–27 deconstruction/reconstruction 18–19 discovery 235–42 elucidation 13–14, 17–18 kit analysis 89 PD098059 141, 143 PED6 207–8 pentaerythritol tetranitrate (PTEN) 65, 127 INDEX 285 pentobarbitol 205 pergolide 143 period1 94 peroxisome proliferator-activated receptors (PPARs) 155, 214 Pfizer 21 PGE2 216 PGH2 212, 214 PGI2 216 PGRP-LC 174 pharmaceutically tractable genome chip 59 Pharmacia & Upjohn 67 pharmacogenomics 55 pharmacological profiling 72 Phenomix 237 phenotype 159–60, 242–4 analysis 66–8 screens 27 phenylephrin 205 phenytoin 143 phorbol esters 157, 158 phorboxazoles 92 phosphatidyl-inositol-dependent protein kinase 1 (PDK-1) 134 phosphoinositol 3-kinase (PI3K) 124, 125, 126, 134 inhibitors 143 phospholipase A 2 (PLA 2) 207–8 phospholipase Cg2 18 phospholipids 31, 204, 214 PI3 kinase inhibitor 143 PI3K 127 Piggybac 103, 104 pinhead screens 131–2 PLA2 214 Pla2g2aI 242 platelet-derived growth factor b 18 platelets 216–17 polycystic kidney disease 45 polymerase chain reaction, quantitative 272 positional cloning 195–7, 244–6 potassium channels 19, 55 PPIases 16 prenyl transferase 22 prepulse inhibition 268–9 presenilin-1 44 presenilins 163, 167–70 Prilosec 253 Prograf 15 propentophyllin 143 prostaglandins 212, 214, 216 prostanoids 204, 205, 212–17 proteasome inhibition 22, 27
286 INDEX protein function 19–22 protein interaction mapping 59 protein tyrosine phosphatase-1B (PTP-1B) 259 proteomics 29–31, 61 Prozac 161–2 PS1 and PS2 163, 170 pseudogenes 60 PTK787 192 purified target-based assays 94–5 pygo 123–4 Qri1 21 quantitative polymerase chain reaction 272 quantitative trait loci (QTL) 240–1 R7 photoreceptors 124–5 Rab23 240 radiation-based mutagenesis 103, 128, 129, 188 radioactive labeling 210–11 Raf pathway 134–5 Raf serine/threonine kinase 124 rag-1 192 random mutagenesis 103–4, 228 Rapamune 15 rapamycin 14, 15, 16–17, 27, 97–8, 143, 144 Ras1 125 Ras farnesyltransferase inhibitors 156 Ras/MAP kinase pathway 124, 126, 158–9 Ras pathway 44–5, 50, 53, 84, 124–6, 134, 158 RBP1 17 receptor tyrosine kinases 84, 88, 124–5 recessive modifier screens 134–5 recessive mutation screens 130–2, 238–40 REDK 19 region-specific screens 240 regulator of G-protein signaling (RGS) proteins 18 Rel/NF-kB 172 Relish 172, 173 Remicade 265 ResGen 25 resistance/sensitivity screen 53 restriction fragment length polymorphisms (RFLPs) 56 retinal axons 186 reverse genetics 87–8, 138–41, 189–91, 224–5, 231–5 rheumatoid arthritis 265 RIKEN 237 RNA-induced silencing complex (RISC) 57 RNA interference (RNAi) technology 46, 56–7, 89–90, 105, 139–41, 170–2 Roche 20 Rosetta Inpharmatics 24 rule-of-five 63 RXRG 216 S2 cells 109, 171, 172–4 26S proteasome 30 Saccharomyces cerevisiae 5 attributes 10–11 common names 10 genome 10–13, 175–6 see also yeast Saccharomyces Genome Database 31, 32 SAG 21 SAHA 98 salicylic acid 155 Sandimmune 15 Sandoz 14–15, 16 SAPK/JNK 22 SB203580 141, 143 scaffold proteins 18 schizophrenia 268, 269, 270 Schizosaccharomyces pombe 10, 14, 18 screen design 242–4 sel-12 167, 170 selective serotonin reuptake inhibitors (SSRIs) 47, 69, 71, 73 selegiline 143 Sem-5 125 sensitized assays 97–8 sensitized screens 241–2 sentinel strains 160–1 SERCA 55 serotonin 47, 48–9, 50, 54, 72–3 Sevenless 124–5 sex determination pathways 84 sex-linked recessive lethal (SLRL) assay 99, 100–1 SHIP2 259 SHIRPA 268 short interfering RNA (siRNA) 57, 90, 272 SHP-2 phosphatase 18 sigma receptor 25 signal transduction pathways 84 signaling pathway conservation 84, 119–27 single nucleotide polymorphisms (SNPs) 55–6, 110, 136 single-stranded conformation polymorphisms (SSCPs) 232
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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 239 and 240: 234 CHEMICAL MUTAGENESIS IN THE MOU
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