Model Organisms in Drug Discovery

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10.5 Conclusions CONCLUSIONS 273 We have described a new conceptual framework for the discovery of drugs with the mammalian genome as starting material. The framework requires genetic antagonism of the drug target combined with a comprehensive in vivo physiological characterization of target function before any chemical screens for pharmaceutical agents are launched. This process constitutes a powerful genetic screen for the targets that allow, ultimately, for maximizing therapeutic effects while minimizing side-effects resulting from therapies modulating the target. In addition, determination of the role of the target in mammalian physiology enables identification of the likely medical indications for the therapeutics to be developed. Although this may appear an obvious prerequisite, it is important to note that many screens are conducted today against molecular targets for which the medical utility is either completely unknown or hypothesized based on only biochemical, gene expression or lower model organism data. The mammalian genetic screen that we have described has been engineered specifically to reveal those genes that encode control points in physiology that may be used to treat major disease processes. Although there are literally thousands of assays that could be incorporated into the screen, we have selected those key tests that measure important medical parameters of physiology that are associated with accepted points of therapeutic intervention and major unmet medical needs. Additionally, the tests must be robust in their application to thousands of animals. Once established, the screen used to discover therapeutic targets can be applied again to demonstrate the efficacy and potential side-effects of candidate therapeutic agents. This broad phenotypic screen, guided by mammalian genetics, provides a new level of power to the preclinical testing of compounds that are developed to interact with chosen targets. The screen enables identification of the key biomarker indicators of efficacy that should be followed when a compound is at the first-time-in-mammal stage. The genetic tools available for preclinical studies include not only wild-type animals but also knock-outs and knock-ins containing the actual human gene targets. The knock-out animals provide guidance for determining the efficacy of novel therapeutic agents. Another powerful aspect of the preclinical testing capabilities includes the treatment of knock-out animals themselves with compounds specific for the target. In such a scenario any effects seen, outside those associated with the knock-out state, are, by definition, off-target sideeffects attributable to the compound itself. Clearly, the ability to manipulate the mouse genome at will provides exciting new opportunities to define accurately the on-target versus off-target side-effects produced by a given agent. Such new approaches are being incorporated into medicinal chemistry strategies to guide lead optimization for the invention of superior therapeutic agents.
274 SATURATION SCREENING OF DRUGGABLE MAMMALIAN GENOME In the post-genome era, a systematic in vivo screen for targets is becoming a necessary precondition for any high-throughput screen to identify smallmolecule therapeutics. The recent revelation of tens of thousands of genes does not necessarily translate to the existence of thousands of drug targets. Strict criteria must be applied to the druggable genome in order to identify the targets for the next-generation breakthrough treatments for human disease. 10.6 References Abdelilah, S., Mountcastle-Shah, E., Harvey, M., Solnica-Krezel, L., Schier, A. F., Stemple, D. L., Malicki, J., et al. (1996). Mutations affecting neural survival in the zebrafish Danio rerio. Development 123, 217–227. Abe, S., Watanabe, H., Hirayama, A., Shibuya, E., Hashimoto, M. and Ide, Y. (2000). Morphological study of the femur in osteopetrotic (op/op) mice using microcomputed tomography. Br. J. Radiol. 73, 1078–1082. Abuin, A., Holt, K. H., Platt, K. A., Sands, A. T. and Zambrowicz, B. P. (2002). Full-speed mammalian genetics: in vivo target validation in the drug discovery process. Trends Biotechnol. 20, 36–42. Accili, D., Drago, J., Lee, E. J., Johnson, M. D., Cool, M. H., Salvatore, P., Asico, L. D., et al. (1996). Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat. Genet. 12, 106–109. Air, E. L., Strowski, M. Z., Benoit, S. C., Conarello, S. L., Salituro, G. M., Guan, X. M., Liu, K., et al. (2002). Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity. Nat. Med. 8, 179–183. Alexander, J. M., Bab, I., Fish, S., Muller, R., Uchiyama, T., Gronowicz, G., Nahounou, M., et al. (2001). Human parathyroid hormone 1-34 reverses bone loss in ovariectomized mice. J Bone Miner. Res. 16, 1665–1673. Baier, H., Klostermann, S., Trowe, T., Karlstrom, R. O., Nusslein-Volhard, C. and Bonhoeffer, F. (1996). Genetic dissection of the retinotectal projection. Development 123, 415–425. Ballou, L. R., Botting, R. M., Goorha, S., Zhang, J. and Vane, J. R. (2000). Nociception in cyclooxygenase isozyme-deficient mice. Proc. Natl. Acad. Sci. USA 97, 10272–10276. Boring, L., Gosling, J., Chensue, S. W., Kunkel, S. L., Farese, R. V., Jr., Broxmeyer, H. E. and Charo, I. F. (1997). Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. J. Clin. Invest. 100, 2552–2561. Brand, M., Heisenberg, C. P., Warga, R. M., Pelegri, F., Karlstrom, R. O., Beuchle, D., Picker, A., Jiang, Y. J., Furutani-Seiki, M., van Eeden, F. J., et al. (1996). Mutations affecting development of the midline and general body shape during zebrafish embryogenesis. Development 123, 129–142. Brockerhoff, S. E., Hurley, J. B., Janssen-Bienhold, U., Neuhauss, S. C., Driever, W. and Dowling, J. E. (1995). A behavioral screen for isolating zebrafish mutants with visual system defects. Proc. Natl. Acad. Sci. USA 92, 10545–10549. Bucay, N., Sarosi, I., Dunstan, C. R., Morony, S., Tarpley, J., Capparelli, C., Scully, S., et al. (1998). Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 12, 1260–1268.
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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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Page 285 and 286: 280 INDEX bupropion 92 busulfan 143
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