Phenotypic screening of the ToxCast chemical library to classify toxic and therapeutic mechanisms

Nature Biotechnology

Volumn 32, Issue 6, 2014, Pages 583-591

  Kleinstreuer, Nicole C ^a   Yang, Jian ^b   Berg, Ellen L ^b   Knudsen, Thomas B ^a   Richard, Ann M ^a   Martin, Matthew T ^a   Reif, David M ^a   Judson, Richard S ^a   Polokoff, Mark ^b   Dix, David J ^a   Kavlock, Robert J ^a   Houck, Keith A ^a  

^a U S ENVIRONMENTAL PROTECTION AGENCY   (United States)

^b BioSeek A Division of DiscoveRx Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHEMICAL ANALYSIS; ENDOTHELIAL CELLS; ENVIRONMENTAL PROTECTION AGENCY; RISK ASSESSMENT; SAFETY TESTING;

ADVERSE OUTCOMES; BIOLOGICAL PATHWAYS; CHEMICAL LIBRARIES; ENVIRONMENTAL CHEMICALS; MODEL ORGANISMS; MOLECULAR FUNCTION; PHENOTYPIC SCREENING; US ENVIRONMENTAL PROTECTION AGENCY;

INDICATORS (CHEMICAL);

CALCINEURIN INHIBITOR; ENVIRONMENTAL CHEMICAL; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; HEAT SHOCK PROTEIN 90 INHIBITOR; HISTAMINE H1 RECEPTOR ANTAGONIST; HISTONE DEACETYLASE INHIBITOR; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; JANUS KINASE INHIBITOR; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; PHOSPHODIESTERASE INHIBITOR; PHOSPHODIESTERASE IV INHIBITOR; PROTEASOME INHIBITOR; PROTEIN KINASE INHIBITOR; RALOXIFENE; SELECTIVE ESTROGEN RECEPTOR MODULATOR; SERUM AMYLOID A; TAMOXIFEN CITRATE; THROMBOPLASTIN; TOXIC SUBSTANCE; TUMOR NECROSIS FACTOR ALPHA;

ADVERSE OUTCOME; ARTICLE; BIOLOGICAL ACTIVITY; BLOOD CLOTTING; CARDIOVASCULAR RISK; CELL SCREENING; CHEMICAL ANALYSIS; CHEMICAL STRUCTURE; CLINICAL PATHWAY; CLUSTER ANALYSIS; CONCENTRATION RESPONSE; CYTOTOXICITY; DRUG DETERMINATION; DRUG MECHANISM; DRUG SCREENING; ENDOTHELIUM CELL; GENETIC TOXICOLOGY; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; MICROTUBULE; OUTCOME ASSESSMENT; PHARMACEUTICAL CARE; PHARMACOLOGICAL PARAMETERS; PHENOTYPE; POLYPHARMACOLOGY; PRIORITY JOURNAL; RISK ASSESSMENT; RISK FACTOR; THROMBOSIS; TOXICITY TESTING; UPREGULATION;

ANIMAL TESTING ALTERNATIVES; ANIMALS; COMPUTER SIMULATION; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; MICE; MODELS, BIOLOGICAL; PHENOTYPE; RATS; SMALL MOLECULE LIBRARIES; TOXICITY TESTS; UNITED STATES; UNITED STATES ENVIRONMENTAL PROTECTION AGENCY;

EID: 84902166194     PISSN: 10870156     EISSN: 15461696     Source Type: Journal    
DOI: 10.1038/nbt.2914     Document Type: Article

References (52)

1. Arrowsmith, J. Trial watch, phase III and submission failures, 2007-2010. Nat. Rev. Drug Discov. 10, 87 (2011).
2. Judson, R. et al. The toxicity data landscape for environmental chemicals. Environ. Health Perspect. 117, 685-695 (2009).
3. National Research Council. Toxicity Testing in the 21st Century: a Vision and a Strategy (National Academies Press, Washington DC, 2007).
4. Bowes, J. et al. Reducing safety-related drug attrition: the use of in vitro pharmacological profiling. Nat. Rev. Drug Discov. 11, 909-922 (2012).
5. Houck, K.A. & Kavlock, R.J. Understanding mechanisms of toxicity: insights from drug discovery research. Toxicol. Appl. Pharmacol. 227, 163-178 (2008).
6. Chen, Y. & Shoichet, B.K. Molecular docking and ligand specificity in fragment-based inhibitor discovery. Nat. Chem. Biol. 5, 358-364 (2009).
7. Kitchen, D.B., Decornez, H., Furr, J.R. & Bajorath, J. Docking and scoring in virtual screening for drug discovery: methods and applications. Nat. Rev. Drug Discov. 3, 935-949 (2004).
8. Lounkine, E. et al. Large-scale prediction and testing of drug activity on side-effect targets. Nature 486, 361-367 (2012).
9. Berg, E., Yang, J. & Polokoff, M. Building predictive models for mechanism of action classification from phenotypic assay datasets. J. Biomol. Screen. 18, 1260-1269 (2013).
10. Berg, E.L., Kunkel, E.J., Hytopoulos, E. & Plavec, I. Characterization of compound mechanisms and secondary activities by BioMAP analysis. J. Pharmacol. Toxicol. Methods 53, 67-74 (2006).
11. Berg, E.L. et al. Chemical target and pathway toxicity mechanisms defined in primary human cell systems. J. Pharmacol. Toxicol. Methods 61, 3-15 (2010).
12. Houck, K.A. et al. Profiling bioactivity of the ToxCast chemical library using BioMAP primary human cell systems. J. Biomol. Screen. 14, 1054-1066 (2009).
13. Kleinstreuer, N.C. et al. Environmental impact on vascular development predicted by high-throughput screening. Environ. Health Perspect. 119, 1596-1603 (2011).
14. Martin, M.T. et al. Predictive model of rat reproductive toxicity from ToxCast high throughput screening. Biol. Reprod. 85, 327-339 (2011).
15. Sipes, N.S. et al. Predictive models of prenatal developmental toxicity from ToxCast high-throughput screening data. Toxicol. Sci. 124, 109-127 (2011).
16. Dix, D.J. et al. The ToxCast program for prioritizing toxicity testing of environmental chemicals. Toxicol. Sci. 95, 5-12 (2007).
17. Kavlock, R. et al. Update on EPA's ToxCast program: providing high throughput decision support tools for chemical risk management. Chem. Res. Toxicol. 25, 1287-1302 (2012).
18. Tice, R.R., Austin, C.P., Kavlock, R.J. & Bucher, J.R. Improving the human hazard characterization of chemicals: a Tox21 update. Environ. Health Perspect. 121, 756-765 (2013).
19. Ayala, A., Parrado, J., Bougria, M. & Machado, A. Effect of oxidative stress, produced by cumene hydroperoxide, on the various steps of protein synthesis: modifications of elongation factor-2. J. Biol. Chem. 271, 23105-23110 (1996).
20. Lau, C. et al. Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. II: postnatal evaluation. Toxicol. Sci. 74, 382-392 (2003).
21. Bogdanska, J. et al. Tissue distribution of (3)(5)S-labelled perfluorooctane sulfonate in adult mice after oral exposure to a low environmentally relevant dose or a high experimental dose. Toxicology 284, 54-62 (2011).
22. Arredondo, J. et al. A receptor-mediated mechanism of nicotine toxicity in oral keratinocytes. Lab. Invest. 81, 1653-1668 (2001).
23. Kleinstreuer, N. et al. A computational model predicting disruption of blood vessel development. PLoS Comput. Biol. 9, e1002996 (2013).
24. Khaidakov, M. et al. Statins and angiogenesis: is it about connections? Biochem. Biophys. Res. Commun. 387, 543-547 (2009).
25. Kohonen, T. Essentials of the self-organizing map. Neural Netw. 37, 52-65 (2013).
26. McCann, F.E. et al. Apremilast, a novel PDE4 inhibitor, inhibits spontaneous production of tumour necrosis factor-alpha from human rheumatoid synovial cells and ameliorates experimental arthritis. Arthritis Res. Ther. 12, R107 (2010).
27. Viguerie, N. et al. Multiple effects of a short-term dexamethasone treatment in human skeletal muscle and adipose tissue. Physiol. Genomics 44, 141-151 (2012).
28. Augustine-Rauch, K.A. et al. Evidence for a molecular mechanism of teratogenicity of SB-236057, a 5-HT1B receptor inverse agonist that alters axial formation. Birth Defects Res. A Clin. Mol. Teratol. 70, 789-807 (2004).
29. Owens, A.P. III & Mackman, N. Role of tissue factor in atherothrombosis. Curr. Atheroscler. Rep. 14, 394-401 (2012).
30. Camici, G.G. et al. Rapamycin promotes arterial thrombosis in vivo: implications for everolimus and zotarolimus eluting stents. Eur. Heart J. 31, 236-242 (2010).
31. Barua, R.S. & Ambrose, J.A. Mechanisms of coronary thrombosis in cigarette smoke exposure. Arterioscler. Thromb. Vasc. Biol. 33, 1460-1467 (2013).
32. Cummings, S.R. et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple outcomes of raloxifene evaluation. J. Am. Med. Assoc. 281, 2189-2197 (1999).
33. Lipton, A., Harvey, H.A. & Hamilton, R.W. Venous thrombosis as a side effect of tamoxifen treatment. Cancer Treat. Rep. 68, 887-889 (1984).
34. Kunkel, E.J. et al. An integrative biology approach for analysis of drug action in models of human vascular inflammation. FASEB J. 18, 1279-1281 (2004).
35. Plavec, I. et al. Method for analyzing signaling networks in complex cellular systems. Proc. Natl. Acad. Sci. USA 101, 1223-1228 (2004).
36. Robichaud, A. et al. Assessing the emetic potential of PDE4 inhibitors in rats. Br. J. Pharmacol. 135, 113-118 (2002).
37. Kirkiacharian, S., Chidiack, H., Philibert, D., Van De Velde, P. & Bouchoux, F. Binding affinity to steroid hormone receptors and antiproliferative action on MCF-7 cells of coumarin derivatives and isoflavonoids. Ann. Pharm. Fr. 57, 332-339 (1999).
38. Barna, T.M. et al. Crystal structure of pentaerythritol tetranitrate reductase: "flipped" binding geometries for steroid substrates in different redox states of the enzyme. J. Mol. Biol. 310, 433-447 (2001).
39. Murotani, T., Ishizuka, T., Isogawa, Y., Karashima, M. & Yamatodani, A. Possible involvement of serotonin 5-HT2 receptor in the regulation of feeding behavior through the histaminergic system. Neuropharmacology 61, 228-233 (2011).
40. Ouattara, B. et al. Changes of AMPA receptors in MPTP monkeys with levodopa-induced dyskinesias. Neuroscience 167, 1160-1167 (2010).
41. Fell, M.J. et al. Activation of metabotropic glutamate (mGlu)2 receptors suppresses histamine release in limbic brain regions following acute ketamine challenge. Neuropharmacology 58, 632-639 (2010).
42. Aizu-Yokota, E., Ichinoseki, K. & Sato, Y. Microtubule disruption induced by estradiol in estrogen receptor-positive and -negative human breast cancer cell lines. Carcinogenesis 15, 1875-1879 (1994).
43. Thiede, A., Gellerich, F.N., Schonfeld, P. & Siemen, D. Complex effects of 17beta-estradiol on mitochondrial function. Biochim. Biophys. Acta 1817, 1747-1753 (2012).
44. Cohen, S.B. et al. Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis. Arthritis Rheum. 60, 335-344 (2009).
45. Ding, C. Drug evaluation: VX-702, a MAP kinase inhibitor for rheumatoid arthritis and acute coronary syndrome. Curr. Opin. Investig. Drugs 7, 1020-1025 (2006).
46. Attene-Ramos, M.S. et al. The Tox21 robotic platform for the assessment of environmental chemicals - from vision to reality. Drug Discov. Today 18, 716-723 (2013).
47. US Environmental Protection Agency. US Environmental Protection Agency Endocrine Disruptor Screening Program Comprehensive Management Plan. http://www.epa.gov/endo/pubs/edsp21-work-plan-summary%20-overview-final.pdf http://www.epa.gov/scipoly/oscpendo/pubs/EDSP-Comprehesive-Management%20Plan- %20021414-f.pdf(Jointly developed by the Office of Chemical Safety & Pollution Prevention and the Office of Water, EPA, 2014).
48. Kunkel, E.J. et al. Rapid structure-activity and selectivity analysis of kinase inhibitors by BioMAP analysis in complex human primary cell-based models. Assay Drug Dev. Technol. 2, 431-442 (2004).
49. Williams, O. et al. Discovery of dual inhibitors of the immune cell PI3Ks p110delta and p110gamma: a prototype for new anti-inflammatory drugs. Chem. Biol. 17, 123-134 (2010).
50. Berg, E.L., Kunkel, E.J. & Hytopoulos, E. Biological complexity and drug discovery: a practical systems biology approach. Syst. Biol. (Stevenage) 152, 201-206 (2005).
51. Melrose, J., Tsurushita, N., Liu, G. & Berg, E.L. IFN-gamma inhibits activation-induced expression of E- and P-selectin on endothelial cells. J. Immunol. 161, 2457-2464 (1998).
52. Clark, R.D., Patterson, D.E., Soltanshahi, F., Blake, J.F. & Matthew, J.B. Visualizing substructural fingerprints. J. Mol. Graphics Model. 18, 404-411 (2000).