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Target Identification: A Challenging Step in Forward Chemical Genetics

  • Das, Raj Kumar (Department of Chemistry, National University of Singapore) ;
  • Samanta, Animesh (Department of Chemistry, National University of Singapore) ;
  • Ghosh, Krishnakanta (Department of Chemistry & MedChem Program of Life Sciences Institute, National University of Singapore) ;
  • Zhai, Duanting (Department of Chemistry & MedChem Program of Life Sciences Institute, National University of Singapore) ;
  • Xu, Wang (Department of Chemistry & MedChem Program of Life Sciences Institute, National University of Singapore) ;
  • Su, Dongdong (Department of Chemistry & MedChem Program of Life Sciences Institute, National University of Singapore) ;
  • Leong, Cheryl (Graduate School for Integrative Sciences and Engineering, National University of Singapore) ;
  • Chang, Young-Tae (Department of Chemistry, National University of Singapore)
  • Received : 2011.01.21
  • Accepted : 2011.01.21
  • Published : 2011.03.31
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Abstract

Investigation of the genetic functions in complex biological systems is a challenging step in recent year. Hence, several valuable and interesting research projects have been developed with novel ideas to find out the unknown functions of genes or proteins. To validate the applicability of their novel ideas, various approaches are built up. To date, the most promising and commonly used approach for discovering the target proteins from biological system using small molecule is well known a forward chemical genetics which is considered to be more convenient than the classical genetics. Although, the forward chemical genetics consists of the three basic components, the target identification is the most challenging step to chemical biology researchers. Hence, the diverse target identification methods have been developed and adopted to disclose the small molecule bound protein. Herein, in this review, we briefly described the first two parts chemical toolbox and screening, and then the target identifications in forward chemical genetics are thoroughly described along with the illustrative real example case study. In the tabular form, the different biological active small molecules which are the successful examples of target identifications are accounted in this research review.

Keywords

References

  1. Witkowski, J. (2010). Long view of the Human Genome Project. Nature 466, 921-922. https://doi.org/10.1038/466921a
  2. Feder, M.E., and Mitchell-Olds, T. (2003). Evolutionary and ecological functional genomics. Nat Rev Genet 4, 651-657. https://doi.org/10.1038/nrm1173
  3. Huttenhower, C., Haley, E.M., Hibbs, M.A., Dumeaux, V., Barrett, D.R., Coller, H.A., and Troyanskaya, O.G. (2009). Exploring the human genome with functional maps. Genome Res 19, 1093-1106. https://doi.org/10.1101/gr.082214.108
  4. Ho, C.H., Piotrowski, J., Dixon, S.J., Baryshnikova, A., Costanzo, M., and Boone, C. (2010). Combining functional genomics and chemical biology to identify targets of bioactive compounds. Curr Opin Chem Biol 15, 1-13.
  5. Stockwell, B.R. (2000). Chemical genetics: ligand-based discovery of gene function. Nat Rev Genet 1, 116-125. https://doi.org/10.1038/35038557
  6. De Rybel, B., Audenaert, D., Beeckman, T., and Kepinski, S. (2009). The past, present, and future of chemical biology in auxin research. ACS Chem Biol 4, 987-998. https://doi.org/10.1021/cb9001624
  7. Chang, Y.T. (2008). Forward Chemical Genetics. Willey Encyclopedia Chem Bio, 1-8.
  8. Neumann, G., Hatta, M., and Kawaoka, Y. (2003). Reverse genetics for the control of avian influenza. Avian Dis 47, 882-887. https://doi.org/10.1637/0005-2086-47.s3.882
  9. Zheng, X.F., and Chan, T.F. (2002). Chemical genomics in the global study of protein functions. Drug Discov Today 7, 197-205. https://doi.org/10.1016/S1359-6446(01)02118-3
  10. Stockwell, B.R., Haggarty, S.J., and Schreiber, S.L. (1999). High-throughput screening of small molecules in miniaturized mammalian cell-based assays involving post-translational modifications. Chem Biol 6, 71-83. https://doi.org/10.1016/S1074-5521(99)80004-0
  11. Stockwell, B.R. (2004). Exploring biology with small organic molecules. Nature 432, 846-854. https://doi.org/10.1038/nature03196
  12. Egener, T., Granado, J., Guitton, M.C., Hohe, A., Holtorf, H., Lucht, J.M., Rensing, S.A., Schlink, K., Schulte, J., Schween, G., et al. (2002). High frequency of phenotypic deviations in Physcomitrella patens plants transformed with a gene-disruption library. BMC Plant Biol 2, 6. https://doi.org/10.1186/1471-2229-2-6
  13. Namy, O., Hatin, I., Stahl, G., Liu, H., Barnay, S., Bidou, L., and Rousset, J.P. (2002). Gene overexpression as a tool for identifying new trans-acting factors involved in translation termination in Saccharomyces cerevisiae. Genetics 161, 585-594.
  14. Koivisto, U.M., Hubbard, A.L., and Mellman, I. (2001). A novel cellular phenotype for familial hypercholesterolemia due to a defect in polarized targeting of LDL receptor. Cell 105, 575-585. https://doi.org/10.1016/S0092-8674(01)00371-3
  15. Ballard, J.W., and Melvin, R.G. (2010). Linking the mitochondrial genotype to the organismal phenotype. Mol Ecol 19, 1523-1539. https://doi.org/10.1111/j.1365-294X.2010.04594.x
  16. Spring, D.R. (2005). Chemical genetics to chemical genomics: small molecules offer big insights. Chem Soc Rev 34, 472-482. https://doi.org/10.1039/b312875j
  17. Kim, Y.K., and Chang, Y.T. (2007). Tagged library approach facilitates forward chemical genetics. Mol Biosyst 3, 392-397. https://doi.org/10.1039/b702321a
  18. Scherer, L.J., and Rossi, J.J. (2003). Approaches for the sequence-specific knockdown of mRNA. Nat Biotechnol 21, 1457-1465. https://doi.org/10.1038/nbt915
  19. Lokey, R.S. (2003). Forward chemical genetics: progress and obstacles on the path to a new pharmacopoeia. Curr Opin Chem Biol 7, 91-96. https://doi.org/10.1016/S1367-5931(02)00002-9
  20. Kidera, A., and Go, N. (1990). Refinement of protein dynamic structure: normal mode refinement. Proc Natl Acad Sci U S A 87, 3718-3722. https://doi.org/10.1073/pnas.87.10.3718
  21. Shapiro, J.A. (1998). Thinking About Bacterial Populations as Multicellular Organisms. Annu Rev Microbiol 52, 81-104. https://doi.org/10.1146/annurev.micro.52.1.81
  22. Ding, S., Wu, T.Y., Brinker, A., Peters, E.C., Hur, W., Gray, N.S., and Schultz, P.G. (2003). Synthetic small molecules that control stem cell fate. Proc Natl Acad Sci U S A 100, 7632-7637. https://doi.org/10.1073/pnas.0732087100
  23. Boshoff, H.I., and Dowd, C.S. (2007). Chemical genetics: an evolving toolbox for target identification and lead optimization. Prog Drug Res 64, 49, 51-77. https://doi.org/10.1007/978-3-7643-7567-6_3
  24. Raikhel, N., and Pirrung, M. (2005). Adding precision tools to the plant biologists' toolbox with chemical genomics. Plant Physiol 138, 563-564. https://doi.org/10.1104/pp.104.900155
  25. Evans, M.J., Saghatelian, A., Sorensen, E.J., and Cravatt, B.F. (2005). Target discovery in small-molecule cell-based screens by in situ proteome reactivity profiling. Nat Biotechnol 23, 1303-1307. https://doi.org/10.1038/nbt1149
  26. Snyder, J.R., Hall, A., Ni-Komatsu, L., Khersonsky, S.M., Chang, Y.T., and Orlow, S.J. (2005). Dissection of melanogenesis with small molecules identifies prohibitin as a regulator. Chem Biol 12, 477-484. https://doi.org/10.1016/j.chembiol.2005.02.014
  27. Warashina, M., Min, K.H., Kuwabara, T., Huynh, A., Gage, F.H., Schultz, P.G., and Ding, S. (2006). A synthetic small molecule that induces neuronal differentiation of adult hippocampal neural progenitor cells. Angew Chem Int Ed Engl 45, 591-593. https://doi.org/10.1002/anie.200503089
  28. Wang, S., and Chang, Y.T. (2008). Discovery of heparin chemosensors through diversity oriented fluorescence library approach. Chem Commun (Camb), 1173-1175.
  29. Wang, S., Kim, Y.K., and Chang, Y.T. (2008). Diversity-oriented fluorescence library approach (DOFLA) to the discovery of chymotrypsin sensor. J Comb Chem 10, 460-465. https://doi.org/10.1021/cc700189b
  30. Wang, S., Kim, Y.K., and Chang, Y.T. (2008). Diversity-oriented fluorescence library approach (DOFLA) to the discovery of chymotrypsin sensor. J Comb Chem 10, 460-465. https://doi.org/10.1021/cc700189b
  31. Lee, J.S., Kim, Y.K., Vendrell, M., and Chang, Y.T. (2009). Diversity-oriented fluorescence library approach for the discovery of sensors and probes. Mol Biosyst 5, 411-421. https://doi.org/10.1039/b821766c
  32. Carlson, E.E. (2010). Natural products as chemical probes. ACS Chem Biol 5, 639-653. https://doi.org/10.1021/cb100105c
  33. Bargagna-Mohan, P., Hamza, A., Kim, Y.E., Khuan Abby Ho, Y., Mor-Vaknin, N., Wendschlag, N., Liu, J., Evans, R.M., Markovitz, D.M., Zhan, C.G., et al. (2007). The tumor inhibitor and antiangiogenic agent withaferin A targets the intermediate filament protein vimentin. Chem Biol 14, 623-634. https://doi.org/10.1016/j.chembiol.2007.04.010
  34. Crews, C.M., Yeh, J., Mohan, R., Meng, L., Kim, K., Splittgerber, U., Kwok, B. H. B., and Elofsson, M. (2000). Natural products as molecular probes: A chemical genetic approach to pharmaceutical target validation. Abstr Pap Am Chem S 219, U480-U480.
  35. Crews, C.M. (2006). Chemical genetics: Using natural products as probes for cell biology. Abstr Pap Am Chem S 231.
  36. Yang, J., Shamji, A., Matchacheep, S., and Schreiber, S.L. (2007). Identification of a small-molecule inhibitor of class Ia PI3Ks with cell-based screening. Chem Biol 14, 371-377. https://doi.org/10.1016/j.chembiol.2007.02.004
  37. Zhang, W., Lu, Y., Hiu-Tung Chen, C., Zeng, L., and Kassel, D.B. (2006). Fluorous mixture synthesis of two libraries with hydantoin-, and benzodiazepinedione-fused heterocyclic scaffolds. J Comb Chem 8, 687-695. https://doi.org/10.1021/cc060061e
  38. Miyazaki, K., Hirase, T., Kojima, Y., and Flint, H.J. (2005). Medium- to large-sized xylo-oligosaccharides are responsible for xylanase induction in Prevotella bryantii B14. Microbiology 151, 4121-4125. https://doi.org/10.1099/mic.0.28270-0
  39. Kelly, K., Alencar, H., Funovics, M., Mahmood, U., and Weissleder, R. (2004). Detection of invasive colon cancer using a novel, targeted, library-derived fluorescent peptide. Cancer Res 64, 6247-6251. https://doi.org/10.1158/0008-5472.CAN-04-0817
  40. Botstein, D., Chervitz, S.A., and Cherry, J.M. (1997). Yeast as a model organism. Science 277, 1259-1260. https://doi.org/10.1126/science.277.5330.1259
  41. Blackwell, H.E., and Zhao, Y. (2003). Chemical genetic approaches to plant biology. Plant Physiol 133, 448-455. https://doi.org/10.1104/pp.103.031138
  42. Rorth, P., Szabo, K., Bailey, A., Laverty, T., Rehm, J., Rubin, G.M., Weigmann, K., Milan, M., Benes, V., Ansorge, W., et al. (1998). Systematic gain-of-function genetics in Drosophila. Development 125, 1049-1057.
  43. Adams, M.D., Celniker, S.E., Holt, R.A., Evans, C.A., Gocayne, J.D., Amanatides, P.G., Scherer, S.E., Li, P.W., Hoskins, R.A., Galle, R.F., et al. (2000). The genome sequence of Drosophila melanogaster. Science 287, 2185-2195. https://doi.org/10.1126/science.287.5461.2185
  44. Lacchini, A.H., Everington, M.L., Augousti , A.T., and Walker, A.J. (2007). Use of C. Elegans as a model organism for sensing the effects of ELF-EMFs. J. Phys.: Conf. Ser. 76, 012027. https://doi.org/10.1088/1742-6596/76/1/012027
  45. Mendoza, L.G., McQuary, P., Mongan, A., Gangadharan, R., Brignac, S., and Eggers, M. (1999). High-throughput microarray-based enzyme-linked immunosorbent assay (ELISA). Biotechniques 27, 778-780, 782-776, 788.
  46. Eggert, U.S., and Mitchison, T.J. (2006). Small molecule screening by imaging. Curr Opin Chem Biol 10, 232-237. https://doi.org/10.1016/j.cbpa.2006.04.010
  47. Guy, R.L., Gonias, L.A., and Stein, M.A. (2000). A fluorescence microscopy based genetic screen to identify mutants altered for interactions with host cells. J Microbiol Methods 42, 129-138. https://doi.org/10.1016/S0167-7012(00)00188-3
  48. Taylor, D.L. (2010). A personal perspective on high-content screening (HCS): from the beginning. J Biomol Screen 15, 720-725. https://doi.org/10.1177/1087057110374995
  49. Khersonsky, S.M., Jung, D.W., Kang, T.W., Walsh, D.P., Moon, H.S., Jo, H., Jacobson, E.M., Shetty, V., Neubert, T.A., and Chang, Y.T. (2003). Facilitated forward chemical genetics using a tagged triazine library and zebrafish embryo screening. J Am Chem Soc 125, 11804-11805. https://doi.org/10.1021/ja035334d
  50. Ahn, Y.H., and Chang, Y.T. (2007). Tagged small molecule library approach for facilitated chemical genetics. Acc Chem Res 40, 1025-1033. https://doi.org/10.1021/ar700030k
  51. McPherson, M., Yang, Y., Hammond, P.W., and Kreider, B.L. (2002). Drug receptor identification from multiple tissues using cellular-derived mRNA display libraries. Chem Biol 9, 691-698. https://doi.org/10.1016/S1074-5521(02)00148-5
  52. Kotake, Y., Sagane, K., Owa, T., Mimori-Kiyosue, Y., Shimizu, H., Uesugi, M., Ishihama, Y., Iwata, M., and Mizui, Y. (2007). Splicing factor SF3b as a target of the antitumor natural product pladienolide. Nat Chem Biol 3, 570-575. https://doi.org/10.1038/nchembio.2007.16
  53. Zhu, S., Wurdak, H., Wang, J., Lyssiotis, C.A., Peters, E.C., Cho, C.Y., Wu, X., and Schultz, P.G. (2009). A small molecule primes embryonic stem cells for differentiation. Cell Stem Cell 4, 416-426. https://doi.org/10.1016/j.stem.2009.04.001
  54. Webb, Y., Zhou, X., Ngo, L., Cornish, V., Stahl, J., Erdjument-Bromage, H., Tempst, P., Rifkind, R.A., Marks, P.A., Breslow, R., et al. (1999). Photoaffinity labeling and mass spectrometry identify ribosomal protein S3 as a potential target for hybrid polar cytodifferentiation agents. J Biol Chem 274, 14280-14287. https://doi.org/10.1074/jbc.274.20.14280
  55. MacKinnon, A.L., Garrison, J.L., Hegde, R.S., and Taunton, J. (2007). Photo-leucine incorporation reveals the target of a cyclodepsipeptide inhibitor of cotranslational translocation. J Am Chem Soc 129, 14560-14561. https://doi.org/10.1021/ja076250y
  56. Wurdak, H., Zhu, S., Min, K.H., Aimone, L., Lairson, L.L., Watson, J., Chopiuk, G., Demas, J., Charette, B., Halder, R., et al. (2010). A small molecule accelerates neuronal differentiation in the adult rat. Proc Natl Acad Sci U S A 107, 16542-16547. https://doi.org/10.1073/pnas.1010300107
  57. Tanaka, H., Ohshima, N., and Hidaka, H. (1999). Isolation of cDNAs encoding cellular drug-binding proteins using a novel expression cloning procedure: drug-western. Mol Pharmacol 55, 356-363. https://doi.org/10.1124/mol.55.2.356
  58. Becker, F., Murthi, K., Smith, C., Come, J., Costa-Roldan, N., Kaufmann, C., Hanke, U., Degenhart, C., Baumann, S., Wallner, W., et al. (2004). A three-hybrid approach to scanning the proteome for targets of small molecule kinase inhibitors. Chem Biol 11, 211-223. https://doi.org/10.1016/S1074-5521(04)00029-8
  59. Eyckerman, S., Verhee, A., der Heyden, J.V., Lemmens, I., Ostade, X.V., Vandekerckhove, J., and Tavernier, J. (2001). Design and application of a cytokine-receptor-based interaction trap. Nat Cell Biol 3, 1114-1119. https://doi.org/10.1038/ncb1201-1114
  60. Caligiuri, M., Molz, L., Liu, Q., Kaplan, F., Xu, J.P., Majeti, J.Z., Ramos-Kelsey, R., Murthi, K., Lievens, S., Tavernier, J., et al. (2006). MASPIT: three-hybrid trap for quantitative proteome fingerprinting of small molecule-protein interactions in mammalian cells. Chem Biol 13, 711-722. https://doi.org/10.1016/j.chembiol.2006.05.008
  61. Jung, J.H., Shim, J.S., Park, J., Ha, H.J., Kim, J.H., Kim, J.G., Kim, N.D., Yoon, J.H., and Kwon, J. (2009). Proteomics Clin. Appl. 3, 423-432. https://doi.org/10.1002/prca.200800060
  62. Hammond, P.W., Alpin, J., Rise, C.E., Wright, M., and Kreider, B.L. (2001). In vitro selection and characterization of Bcl-X(L)-binding proteins from a mix of tissue-specific mRNA display libraries. J Biol Chem 276, 20898-20906. https://doi.org/10.1074/jbc.M011641200
  63. Lipovsek, D., and Pluckthun, A. (2004). In-vitro protein evolution by ribosome display and mRNA display. J Immunol Methods 290, 51-67. https://doi.org/10.1016/j.jim.2004.04.008
  64. Liu, R., Barrick, J.E., Szostak, J.W., and Roberts, R.W. (2000). Optimized synthesis of RNA-protein fusions for in vitro protein selection. Methods Enzymol 318, 268-293. https://doi.org/10.1016/S0076-6879(00)18058-9
  65. Kino, T., Hatanaka, H., Hashimoto, M., Nishiyama, M., Goto, T., Okuhara, M., Kohsaka, M., Aoki, H., and Imanaka, H. (1987). FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) 40, 1249-1255. https://doi.org/10.7164/antibiotics.40.1249
  66. MacBeath, G., and Schreiber, S.L. (2000). Printing proteins as microarrays for high-throughput function determination. Science 289, 1760-1763.
  67. Zhu, H., and Snyder, M. (2003). Protein chip technology. Curr Opin Chem Biol 7, 55-63. https://doi.org/10.1016/S1367-5931(02)00005-4
  68. Astle, J.M., Simpson, L.S., Huang, Y., Reddy, M.M., Wilson, R., Connell, S., Wilson, J., and Kodadek, T. (2010). Seamless bead to microarray screening: rapid identification of the highest affinity protein ligands from large combinatorial libraries. Chem Biol 17, 38-45. https://doi.org/10.1016/j.chembiol.2009.12.015
  69. Huang, J., Zhu, H., Haggarty, S.J., Spring, D.R., Hwang, H., Jin, F., Snyder, M., and Schreiber, S.L. (2004). Finding new components of the target of rapamycin (TOR) signaling network through chemical genetics and proteome chips. Proc Natl Acad Sci U S A 101, 16594-16599. https://doi.org/10.1073/pnas.0407117101
  70. Lomenick, B., Hao, R., Jonai, N., Chin, R.M., Aghajan, M., Warburton, S., Wang, J., Wu, R.P., Gomez, F., Loo, J.A., et al. (2009). Target identification using drug affinity responsive target stability (DARTS). Proc Natl Acad Sci U S A 106, 21984-21989. https://doi.org/10.1073/pnas.0910040106
  71. Lomenick, B., Olsen, R.W., and Huang, J. (2011). Identification of direct protein targets of small molecules. ACS Chem Biol 6, 34-46. https://doi.org/10.1021/cb100294v
  72. Swoboda, J.G., Meredith, T.C., Campbell, J., Brown, S., Suzuki, T., Bollenbach, T., Malhowski, A.J., Kishony, R., Gilmore, M.S., and Walker, S. (2009). Discovery of a small molecule that blocks wall teichoic acid biosynthesis in Staphylococcus aureus. ACS Chem Biol 4, 875-883. https://doi.org/10.1021/cb900151k
  73. Won, J., Kim, M., Yi, Y.W., Kim, Y.H., Jung, N., and Kim, T.K. (2005). A magnetic nanoprobe technology for detecting molecular interactions in live cells. Science 309, 121-125. https://doi.org/10.1126/science.1112869
  74. Won, J., Kim, M., Kim, N., Ahn, J.H., Lee, W.G., Kim, S.S., Chang, K.Y., Yi, Y.W., and Kim, T.K. (2006). Small molecule-based reversible reprogramming of cellular lifespan. Nat Chem Biol 2, 369-374. https://doi.org/10.1038/nchembio800
  75. Nakai, R., Iida, S., Takahashi, T., Tsujita, T., Okamoto, S., Takada, C., Akasaka, K., Ichikawa, S., Ishida, H., Kusaka, H., et al. (2009). K858, a novel inhibitor of mitotic kinesin Eg5 and antitumor agent, induces cell death in cancer cells. Cancer Res 69, 3901-3909. https://doi.org/10.1158/0008-5472.CAN-08-4373
  76. Nagumo, Y., Kakeya, H., Shoji, M., Hayashi, Y., Dohmae, N., and Osada, H. (2005). Epolactaene binds human Hsp60 Cys442 resulting in the inhibition of chaperone activity. Biochem J 387, 835-840. https://doi.org/10.1042/BJ20041355
  77. Misra-press, A., McMillan, M., Cudaback, E., Qabar, M., Ruan, F., Nguyen, M., Vaisar, T., Nakanishi, H., and Kahn, M. (2002). Identification of a Novel Inhibitor of the NF-kB Pathway. Curr. Med. Chem. - Anti-Inflammatory & Anti-Allergy Agents 1, 29-39. https://doi.org/10.2174/1568014024606566
  78. Bedalov, A., Gatbonton, T., Irvine, W.P., Gottschling, D.E., and Simon, J.A. (2001). Identification of a small molecule inhibitor of Sir2p. Proc Natl Acad Sci U S A 98, 15113-15118. https://doi.org/10.1073/pnas.261574398
  79. Butcher, R.A., and Schreiber, S.L. (2003). A small molecule suppressor of FK506 that targets the mitochondria and modulates ionic balance in Saccharomyces cerevisiae. Chem Biol 10, 521-531. https://doi.org/10.1016/S1074-5521(03)00108-X
  80. Butcher, R.A., and Schreiber, S.L. (2004). Identification of Ald6p as the target of a class of small-molecule suppressors of FK506 and their use in network dissection. Proc Natl Acad Sci U S A 101, 7868-7873. https://doi.org/10.1073/pnas.0402317101
  81. Grozinger, C.M., Chao, E.D., Blackwell, H.E., Moazed, D., and Schreiber, S.L. (2001). Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J Biol Chem 276, 38837-38843. https://doi.org/10.1074/jbc.M106779200
  82. Zhao, Y., Dai, X., Blackwell, H.E., Schreiber, S.L., and Chory, J. (2003). SIR1, an upstream component in auxin signaling identified by chemical genetics. Science 301, 1107-1110. https://doi.org/10.1126/science.1084161
  83. Asami, T., Mizutani, M., Fujioka, S., Goda, H., Min, Y.K., Shimada, Y., Nakano, T., Takatsuto, S., Matsuyama, T., Nagata, N., et al. (2001). Selective interaction of triazole derivatives with DWF4, a cytochrome P450 monooxygenase of the brassinosteroid biosynthetic pathway, correlates with brassinosteroid deficiency in planta. J Biol Chem 276, 25687-25691. https://doi.org/10.1074/jbc.M103524200
  84. Drevs, J., Hofmann, I., Hugenschmidt, H., Wittig, C., Madjar, H., Muller, M., Wood, J., Martiny-Baron, G., Unger, C., and Marme, D. (2000). Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. Cancer Res 60, 4819-4824.
  85. Moon, H.S., Jacobson, E.M., Khersonsky, S.M., Luzung, M.R., Walsh, D.P., Xiong, W., Lee, J.W., Parikh, P.B., Lam, J.C., Kang, T.W., et al. (2002). A novel microtubule destabilizing entity from orthogonal synthesis of triazine library and zebrafish embryo screening. J Am Chem Soc 124, 11608-11609. https://doi.org/10.1021/ja026720i
  86. Kao, R.Y., Tsui, W.H., Lee, T.S., Tanner, J.A., Watt, R.M., Huang, J.D., Hu, L., Chen, G., Chen, Z., Zhang, L., et al. (2004). Identification of novel small-molecule inhibitors of severe acute respiratory syndrome-associated coronavirus by chemical genetics. Chem Biol 11, 1293-1299. https://doi.org/10.1016/j.chembiol.2004.07.013
  87. Rosania, G.R., Chang, Y.T., Perez, O., Sutherlin, D., Dong, H., Lockhart, D.J., and Schultz, P.G. (2000). Myoseverin, a microtubule-binding molecule with novel cellular effects. Nat Biotechnol 18, 304-308. https://doi.org/10.1038/73753
  88. Perez, O.D., Chang, Y.T., Rosania, G., Sutherlin, D., and Schultz, P.G. (2002). Inhibition and reversal of myogenic differentiation by purine-based microtubule assembly inhibitors. Chem Biol 9, 475-483. https://doi.org/10.1016/S1074-5521(02)00131-X
  89. Haggarty, S.J., Mayer, T.U., Miyamoto, D.T., Fathi, R., King, R.W., Mitchison, T.J., and Schreiber, S.L. (2000). Dissecting cellular processes using small molecules: identification of colchicine-like, taxol-like and other small molecules that perturb mitosis. Chem Biol 7, 275-286. https://doi.org/10.1016/S1074-5521(00)00101-0
  90. Haggarty, S.J., Koeller, K.M., Wong, J.C., Grozinger, C.M., and Schreiber, S.L. (2003). Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci U S A 100, 4389-4394. https://doi.org/10.1073/pnas.0430973100
  91. Mayer, T.U., Kapoor, T.M., Haggarty, S.J., King, R.W., Schreiber, S.L., and Mitchison, T.J. (1999). Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286, 971-974. https://doi.org/10.1126/science.286.5441.971
  92. Williams, D., Jung, D.W., Khersonsky, S.M., Heidary, N., Chang, Y.T., and Orlow, S.J. (2004). Identification of compounds that bind mitochondrial F1F0 ATPase by screening a triazine library for correction of albinism. Chem Biol 11, 1251-1259. https://doi.org/10.1016/j.chembiol.2004.06.013
  93. Emami, K.H., Nguyen, C., Ma, H., Kim, D.H., Jeong, K.W., Eguchi, M., Moon, R.T., Teo, J.L., Kim, H.Y., Moon, S.H., et al. (2004). A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc Natl Acad Sci U S A 101, 12682-12687. https://doi.org/10.1073/pnas.0404875101
  94. Chong, T., McMillan, M., Teo, J.L., Henderson, J.W.R., and Kahn, M. (2004). Chemogenomic Investigation of AP-1 Transcriptional Regulation of LTC4 Synthase Expression. Lett Drug Des Discovery 1, 211-216. https://doi.org/10.2174/1570180043398920
  95. Jonathan, B.W. (2002)). An approach using 'chemical genetics' has identified small-molecule agonists of the Hedgehog signaling pathway that may lead the way to drugs for chronic degenerative diseases. Journal of Biology 1, 1-7. https://doi.org/10.1186/1475-4924-1-1
  96. Peterson, J.R., Lokey, R.S., Mitchison, T.J., and Kirschner, M.W. (2001). A chemical inhibitor of N-WASP reveals a new mechanism for targeting protein interactions. Proc Natl Acad Sci U S A 98, 10624-10629. https://doi.org/10.1073/pnas.201393198
  97. Peterson, J.R., Bickford, L.C., Morgan, D., Kim, A.S., Ouerfelli, O., Kirschner, M.W., and Rosen, M.K. (2004). Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation. Nat Struct Mol Biol 11, 747-755. https://doi.org/10.1038/nsmb796
  98. Verma, R., Peters, N.R., D'Onofrio, M., Tochtrop, G.P., Sakamoto, K.M., Varadan, R., Zhang, M., Coffino, P., Fushman, D., Deshaies, R.J., et al. (2004). Ubistatins inhibit proteasome-dependent degradation by binding the ubiquitin chain. Science 306, 117-120. https://doi.org/10.1126/science.1100946
  99. Wignall, S.M., Gray, N.S., Chang, Y.T., Juarez, L., Jacob, R., Burlingame, A., Schultz, P.G., and Heald, R. (2004). Identification of a novel protein regulating microtubule stability through a chemical approach. Chem Biol 11, 135-146. https://doi.org/10.1016/j.chembiol.2003.12.019
  100. Min, J., Kyung Kim, Y., Cipriani, P.G., Kang, M., Khersonsky, S.M., Walsh, D.P., Lee, J.Y., Niessen, S., Yates, J.R., 3rd, Gunsalus, K., et al. (2007). Forward chemical genetic approach identifies new role for GAPDH in insulin signaling. Nat Chem Biol 3, 55-59. https://doi.org/10.1038/nchembio833
  101. Gao, M., Nettles, R.E., Belema, M., Snyder, L.B., Nguyen, V.N., Fridell, R.A., Serrano-Wu, M.H., Langley, D.R., Sun, J.H., O'Boyle, D.R., 2nd, et al. (2010). Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 465, 96-100. https://doi.org/10.1038/nature08960
  102. Lee, M.Y., Kim, M.H., Kim, J., Kim, S.H., Kim, B.T., Jeong, I.H., Chang, S., and Chang, S.Y. (2010). Synthesis and SAR of sulfonyl- and phosphoryl amidine compounds as anti-resorptive agents. Bioorg Med Chem Lett 20, 541-545. https://doi.org/10.1016/j.bmcl.2009.11.104
  103. Chang, S.Y., Bae, S.J., Lee, M.Y., Baek, S.H., Chang, S., and Kim, S.H. (2011). Chemical affinity matrix-based identification of prohibitin as a binding protein to anti-resorptive sulfonyl amidine compounds. Bioorg Med Chem Lett 21, 727-729. https://doi.org/10.1016/j.bmcl.2010.11.123
  104. Zhang, Q., Major, M.B., Takanashi, S., Camp, N.D., Nishiya, N., Peters, E.C., Ginsberg, M.H., Jian, X., Randazzo, P.A., Schultz, P.G., et al. (2007). Small-molecule synergist of the Wnt/beta-catenin signaling pathway. Proc Natl Acad Sci U S A 104, 7444-7448. https://doi.org/10.1073/pnas.0702136104
  105. Chen, S., Do, J.T., Zhang, Q., Yao, S., Yan, F., Peters, E.C., Scholer, H.R., Schultz, P.G., and Ding, S. (2006). Self-renewal of embryonic stem cells by a small molecule. Proc Natl Acad Sci U S A 103, 17266-17271. https://doi.org/10.1073/pnas.0608156103
  106. Choi, Y., Shimogawa, H., Murakami, K., Ramdas, L., Zhang, W., Qin, J., and Uesugi, M. (2006). Chemical genetic identification of the IGF-linked pathway that is mediated by STAT6 and MFP2. Chem Biol 13, 241-249. https://doi.org/10.1016/j.chembiol.2005.12.011

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