The development of high-content screening (HCS) technology and its importance to drug discovery

References

• Giuliano KA, Haskins JR, Giuliano KA. High content screening: a powerful approach to systems cell biology and drug discovery. Totowa, NJ: Humana Press; 2010.
   Google Scholar
• Gasparri F. An overview of cell phenotypes in HCS: limitations and advantages. Expert Opin Drug Discov. 2009;4:643–657.
   PubMed Web of Science ®Google Scholar
• Taylor DL. A personal perspective on high-content screening (HCS): from the beginning. J Biomol Screen. 2010;15:720–725.
   PubMed Web of Science ®Google Scholar
• Clatch RJ, Walloch JL, Foreman JR, et al. Multiparameter analysis of DNA content and cytokeratin expression in breast carcinoma by laser scanning cytometry. Arch Pathol Lab Med. 1997;121:585–592.
   PubMed Web of Science ®Google Scholar
• Giuliano KA, Taylor DL. Fluorescent-protein biosensors: new tools for drug discovery. Trends Biotechnol. 1998;16:135–140. doi:10.1016/S0167-7799(97)01166-9.
   PubMed Web of Science ®Google Scholar
• Giuliano KA, DeBiasio RL, Dunlay RT, et al. High content screening: a new approach to easing key bottlenecks in the drug discovery process. J Biomol Screen. 1997;2:249–259.
   Web of Science ®Google Scholar
• Ding GJ, Fischer PA, Boltz RC, et al. Characterization and quantitation of NF-kappaB nuclear translocation induced by interleukin-1 and tumor necrosis factor-alpha. Development and use of a high capacity fluorescence cytometric system. J Biol Chem. 1998;273:28897–28905.
   PubMed Web of Science ®Google Scholar
• Ghosh RN, Chen YT, DeBiasio R, et al. Cell-based, high-content screen for receptor internalization, recycling and intracellular trafficking. Biotechniques. 2000;29:170–175.
   PubMed Web of Science ®Google Scholar
• Gasparri F, Mariani M, Sola F, et al. Quantification of the proliferation index of human dermal fibroblast cultures with the ArrayScan high-content screening reader. J Biomol Screen. 2004;9:232–243.
   PubMed Web of Science ®Google Scholar
• Giuliano KA, Haskins JR, Taylor DL. Advances in high content screening for drug discovery. Assay Drug Dev Technol. 2003;1:565–577. doi:10.1089/154065803322302826.
   PubMed Web of Science ®Google Scholar
• Perlman ZE, Slack MD, Feng Y, et al. Multidimensional drug profiling by automated microscopy. Science. 2004;306:1194–1198.
   PubMed Web of Science ®Google Scholar
• Carpenter AE, Jones TR, Lamprecht MR, et al. Cell Profiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol. 2006;7:R100.
   PubMed Web of Science ®Google Scholar
• Gough AH, Johnston PA. Requirements, features, and performance of high content screening platforms. Methods Mol Biol. 2007;356:41–61.
   PubMedGoogle Scholar
• Swinney DC, Anthony J. How were new medicines discovered? Nat Rev Drug Discov. 2011;10:507–519.
   PubMed Web of Science ®Google Scholar
• Eder J, Sedrani R, Wiesmann C. The discovery of first-in-class drugs: origins and evolution. Nat Rev Drug Discov. 2014;13:577–587.
   PubMed Web of Science ®Google Scholar
• Lee JA, Chu S, Willard FS, et al. Open innovation for phenotypic drug discovery: the PD2 assay panel. J Biomol Screen. 2011;16:588–602. doi:10.1177/1087057111405379.
   PubMed Web of Science ®Google Scholar
• Lee JA, Berg EL. Neoclassic drug discovery: the case for lead generation using phenotypic and functional approaches. J Biomol Screen. 2013;18:1143–1155. doi:10.1177/1087057113506118.
   PubMed Web of Science ®Google Scholar
• Carver J, Dexheimer TS, Hsu D, et al. A high-throughput assay for small molecule destabilizers of the KRAS oncoprotein. PLoS One. 2014;9:e103836. doi:10.1371/journal.pone.0103836.
   Google Scholar
• Gasparri F, Galvani A. Image-based high-content reporter assays: limitations and advantages. Drug Discov Today Technol. 2010;7:e1–e94. doi:10.1016/j.ddtec.2010.04.003.
   Google Scholar
• Kurita KL, Linington RG. Connecting phenotype and chemotype: high-content discovery strategies for natural products research. J Nat Prod. 2015;78:587–596.
   PubMed Web of Science ®Google Scholar
• Begley CG, Ellis LM. Drug development: raise standards for preclinical cancer research. Nature. 2012;483:531–533. doi:10.1038/483531a.
   PubMed Web of Science ®Google Scholar
• Nijman SM. Functional genomics to uncover drug mechanism of action. Nat Chem Biol. 2015;11:942–948. doi:10.1038/nchembio.1963.
   PubMed Web of Science ®Google Scholar
• Carpenter AE. Image-based chemical screening. Nat Chem Biol. 2007;3:461–465. doi:10.1038/nchembio.2007.15.
   PubMed Web of Science ®Google Scholar
• Low J, Stancato L, Lee J, et al. Prioritizing hits from phenotypic high-content screens. Curr Opin Drug Discov Devel. 2008;11:338–345.
   PubMed Web of Science ®Google Scholar
• Mouchet EH, Simpson PB. High-content assays in oncology drug discovery: opportunities and challenges. IDrugs. 2008;11:422–427.
   PubMed Web of Science ®Google Scholar
• Etzion Y, Muslin AJ. The application of phenotypic high-throughput screening techniques to cardiovascular research. Trends Cardiovasc Med. 2009;19:207–212. doi:10.1016/j.tcm.2009.12.006.
   PubMed Web of Science ®Google Scholar
• Zock JM. Applications of high content screening in life science research. Comb Chem High Throughput Screen. 2009;12:870–876.
   PubMed Web of Science ®Google Scholar
• Bickle M. The beautiful cell: high-content screening in drug discovery. Anal Bioanal Chem. 2010;398:219–226. doi:10.1007/s00216-010-3788-3.
   PubMed Web of Science ®Google Scholar
• Michelini E, Cevenini L, Mezzanotte L, et al. Cell-based assays: fuelling drug discovery. Anal Bioanal Chem. 2010;398:227–238. doi:10.1007/s00216-010-3933-z.
   PubMed Web of Science ®Google Scholar
• Westwick JK, Lamerdin JE. Improving drug discovery with contextual assays and cellular systems analysis. Methods Mol Biol. 2011;756:61–73. doi:10.1007/978-1-61779-160-4_3.
   PubMedGoogle Scholar
• Xia X, Wong ST. Concise review: a high-content screening approach to stem cell research and drug discovery. Stem Cells. 2012;30:1800–1807. doi:10.1002/stem.1168.
   PubMed Web of Science ®Google Scholar
• Zheng W, Thorne N, McKew JC. Phenotypic screens as a renewed approach for drug discovery. Drug Discov Today. 2013;18:1067–1073. doi:10.1016/j.drudis.2013.07.001.
   PubMed Web of Science ®Google Scholar
• Martinez NJ, Titus SA, Wagner AK, et al. High-throughput fluorescence imaging approaches for drug discovery using in vitro and in vivo three-dimensional models. Expert Opin Drug Discov. 2015;10:1347–1361.
   PubMed Web of Science ®Google Scholar
• Nierode G, Kwon PS, Dordick JS, et al. Cell-based assay design for high-content screening of drug candidates. J Microbiol Biotechnol. 2015. published online 2015 Oct 2. doi:10.4014/jmb.1508.08007.
   Web of Science ®Google Scholar
• Li L, Zhou Q, Voss TC, et al. High-throughput imaging: focusing in on drug discovery in 3D. Methods. 2015;96:97–102.
   Web of Science ®Google Scholar
• Zhang J, Campbell RE, Ting AY, et al. Creating new fluorescent probes for cell biology. Nat Rev Mol Cell Biol. 2002;3:906–918. doi:10.1038/nrm976.
   PubMed Web of Science ®Google Scholar
• Giepmans BN, Adams SR, Ellisman MH, et al. The fluorescent toolbox for assessing protein location and function. Science. 2006;312:217–224. doi:10.1126/science.1124618.
   PubMed Web of Science ®Google Scholar
• Hughes P, Marshall D, Reid Y, et al. The costs of using unauthenticated, over-passaged cell lines: how much more data do we need? Biotechniques. 2007;43:575–584.
   PubMed Web of Science ®Google Scholar
• Vasudevan C, Fursov N, Maunder P, et al. Improving high-content-screening assay performance by using division-arrested cells. Assay Drug Dev Technol. 2005;3:515–523. doi:10.1089/adt.2005.3.515.
   PubMed Web of Science ®Google Scholar
• Sharma P, Ando DM, Daub A, et al. High-throughput screening in primary neurons. Methods Enzymol. 2012;506:331–360. doi:10.1016/B978-0-12-391856-7.00041-X.
   PubMed Web of Science ®Google Scholar
• Lapan P, Zhang J, Hill A, et al. Image-based assessment of growth and signaling changes in cancer cells mediated by direct cell-cell contact. PLoS One. 2009;4:e6822. doi:10.1371/journal.pone.0006822.
   Google Scholar
• Krausz E, De Hoogt R, Gustin E, et al. Translation of a tumor microenvironment mimicking 3D tumor growth co-culture assay platform to high-content screening. J Biomol Screen. 2013;18:54–66. doi:10.1177/1087057112456874.
   PubMed Web of Science ®Google Scholar
• Tabata Y, Murai N, Sasaki T, et al. Multiparametric phenotypic screening system for profiling bioactive compounds using human fetal hippocampal neural stem/progenitor cells. J Biomol Screen. 2015;20:1074–1083. doi:10.1177/1087057115598119.
   PubMed Web of Science ®Google Scholar
• Alves H, Dechering K, Van Blitterswijk C, et al. High-throughput assay for the identification of compounds regulating osteogenic differentiation of human mesenchymal stromal cells. PLoS One. 2011;6:e26678. doi:10.1371/journal.pone.0026678.
   Google Scholar
• Spiering S, Davidovics H, Bushway PJ, et al. High content screening for modulators of cardiac differentiation in human pluripotent stem cells. Methods Mol Biol. 2015;1263:43–61. doi:10.1007/978-1-4939-2269-7_4.
   PubMedGoogle Scholar
• Yoo BH, Axlund SD, Kabos P, et al. A high-content assay to identify small-molecule modulators of a cancer stem cell population in luminal breast cancer. J Biomol Screen. 2012;17:1211–1220. doi:10.1177/1087057112452138.
   PubMed Web of Science ®Google Scholar
• Carlson C, Koonce C, Aoyama N, et al. Phenotypic screening with human iPS cell-derived cardiomyocytes: HTS-compatible assays for interrogating cardiac hypertrophy. J Biomol Screen. 2013;18:1203–1211. doi:10.1177/1087057113500812.
   PubMed Web of Science ®Google Scholar
• Drawnel FM, Boccardo S, Prummer M, et al. Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells. Cell Rep. 2014;9:810–821. doi:10.1016/j.celrep.2014.09.055.
   PubMed Web of Science ®Google Scholar
• Kaufmann M, Schuffenhauer A, Fruh I, et al. High-throughput screening using iPSC-derived neuronal progenitors to identify compounds counteracting epigenetic gene silencing in fragile X syndrome. J Biomol Screen. 2015;20:1101–1111. doi:10.1177/1087057115588287.
   PubMed Web of Science ®Google Scholar
• Grimm FA, Iwata Y, Sirenko O, et al. High-content assay multiplexing for toxicity screening in induced pluripotent stem cell-derived cardiomyocytes and hepatocytes. Assay Drug Dev Technol. 2015;13:529–546.
   PubMed Web of Science ®Google Scholar
• Andrews PD, Becroft M, Aspegren A, et al. High-content screening of feeder-free human embryonic stem cells to identify pro-survival small molecules. Biochem J. 2010;432:21–33. doi:10.1042/BJ20101022.
   PubMed Web of Science ®Google Scholar
• Hartenian E, Doench JG. Genetic screens and functional genomics using CRISPR/Cas9 technology. Febs J. 2015;282:1383–1393. doi:10.1111/febs.13248.
   PubMed Web of Science ®Google Scholar
• Di Nicolantonio F, Arena S, Gallicchio M, et al. Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses. Proc Natl Acad Sci USA. 2008;105:20864–20869. doi:10.1073/pnas.0808757105.
   PubMed Web of Science ®Google Scholar
• Agrotis A, Ketteler R. A new age in functional genomics using CRISPR/Cas9 in arrayed library screening. Front Genet. 2015;6:300. doi:10.3389/fgene.2015.00360.
   PubMed Web of Science ®Google Scholar
• Shalem O, Sanjana NE, Zhang F. High-throughput functional genomics using CRISPR-Cas9. Nat Rev Genet. 2015;16:299–311.
   PubMed Web of Science ®Google Scholar
• Barouch-Bentov R, Sauer K. Mechanisms of drug resistance in kinases. Expert Opin Investig Drugs. 2011;20:153–208. doi:10.1517/13543784.2011.546344.
   PubMed Web of Science ®Google Scholar
• Hirschhaeuser F, Menne H, Dittfeld C, et al. Multicellular tumor spheroids: an underestimated tool is catching up again. J Biotechnol. 2010;148:3–15. doi:10.1016/j.jbiotec.2010.01.012.
   PubMed Web of Science ®Google Scholar
• Reid BG, Jerjian T, Patel P, et al. Live multicellular tumor spheroid models for high-content imaging and screening in cancer drug discovery. Curr Chem Genom Transl Med. 2014;8:27–35. doi:10.2174/2213988501408010027.
   PubMedGoogle Scholar
• Celli JP, Rizvi I, Blanden AR, et al. An imaging-based platform for high-content, quantitative evaluation of therapeutic response in 3D tumour models. Sci Rep. 2014;4:3751. doi:10.1038/srep03751.
   PubMed Web of Science ®Google Scholar
• Burgstaller G, Oehrle B, Koch I, et al. Multiplex profiling of cellular invasion in 3D cell culture models. PLoS One. 2013;8:e63121. doi:10.1371/journal.pone.0063121.
   Google Scholar
• Wenzel C, Otto S, Prechtl S, et al. A novel 3D high-content assay identifies compounds that prevent fibroblast invasion into tissue surrogates. Exp Cell Res. 2015;339:35–43. doi:10.1016/j.yexcr.2015.10.003.
   PubMed Web of Science ®Google Scholar
• Wenzel C, Riefke B, Gründemann S, et al. 3D high-content screening for the identification of compounds that target cells in dormant tumor spheroid regions. Exp Cell Res. 2014;323:131–143. doi:10.1016/j.yexcr.2014.01.017.
   PubMed Web of Science ®Google Scholar
• Anastasov N, Höfig I, Radulović V, et al. A 3D-microtissue-based phenotypic screening of radiation resistant tumor cells with synchronized chemotherapeutic treatment. BMC Cancer. 2015;15:466. doi:10.1186/s12885-015-1584-3.
   PubMed Web of Science ®Google Scholar
• Hynds RE, Giangreco A. Concise review: the relevance of human stem cell-derived organoid models for epithelial translational medicine. Stem Cells. 2013;31:417–422. doi:10.1002/stem.1290.
   PubMed Web of Science ®Google Scholar
• Ranga A, Gjorevski N, Lutolf MP. Drug discovery through stem cell-based organoid models. Adv Drug Deliv Rev. 2014;69-70:19–28. doi:10.1016/j.addr.2014.02.006.
   PubMed Web of Science ®Google Scholar
• Walsh AJ, Cook RS, Sanders ME, et al. Quantitative optical imaging of primary tumor organoid metabolism predicts drug response in breast cancer. Cancer Res. 2014;74:5184–5194. doi:10.1158/0008-5472.CAN-14-0663.
   PubMed Web of Science ®Google Scholar
• Ohnuki S, Oka S, Nogami S, et al. High-content, image-based screening for drug targets in yeast. PLoS One. 2010;5:e10177. doi:10.1371/journal.pone.0010177.
   Google Scholar
• Saydmohammed M, Vollmer LL, Onuoha EO, et al. A high-content screening assay in transgenic zebrafish identifies two novel activators of fgf signaling. Birth Defects Res C Embryo Today. 2011;93:281–287. doi:10.1002/bdrc.20216.
   PubMed Web of Science ®Google Scholar
• Wittmann C, Reischl M, Shah AH, et al. Facilitating drug discovery: an automated high-content inflammation assay in zebrafish. J Vis Exp. 2012;65:e4203. doi:10.3791/4026.
   Google Scholar
• Sanker S, Cirio MC, Vollmer LL, et al. Development of high-content assays for kidney progenitor cell expansion in transgenic zebrafish. J Biomol Screen. 2013;18:1193–1202. doi:10.1177/1087057113495296.
   PubMed Web of Science ®Google Scholar
• Yozzo KL, Isales GM, Raftery TD, et al. High-content screening assay for identification of chemicals impacting cardiovascular function in zebrafish embryos. Environ Sci Technol. 2013;47:11302–11310. doi:10.1021/es403360y.
   PubMed Web of Science ®Google Scholar
• Tomlinson ML, Hendry AE, Wheeler GN. Chemical genetics and drug discovery in Xenopus. Methods Mol Biol. 2012;917:155–166. doi:10.1007/978-1-61779-992-1_9.
   PubMedGoogle Scholar
• Schmitt SM, Gull M, Brändli AW. Engineering Xenopus embryos for phenotypic drug discovery screening. Adv Drug Deliv Rev. 2014;69-70:225–246.
   PubMed Web of Science ®Google Scholar
• Gosai SJ, Kwak JH, Luke CJ, et al. Automated high-content live animal drug screening using C. elegans expressing the aggregation prone serpin α1-antitrypsin Z. PLoS One. 2010;5(11):e15460.
   PubMed Web of Science ®Google Scholar
• O’Reilly LP, Luke CJ, Perlmutter DH, et al. C. elegans in high-throughput drug discovery. Adv Drug Deliv Rev. 2014;69-70:247–253. doi:10.1016/j.addr.2013.12.001.
   PubMed Web of Science ®Google Scholar
• Kobet RA, Pan X, Zhang B, et al. Caenorhabditis elegans: a model system for anti-cancer drug discovery and therapeutic target identification. Biomol Ther (Seoul). 2014;22:371–383. doi:10.4062/biomolther.2014.084.
   PubMed Web of Science ®Google Scholar
• Gasparri F, Sola F, Bandiera T, et al. High-content analysis of kinase activity in cells. Comb Chem High Throughput Screen. 2008;11:523–536.
   PubMed Web of Science ®Google Scholar
• Senutovitch N, Vernetti L, Boltz R, et al. Fluorescent protein biosensors applied to microphysiological systems. Exp Biol Med (Maywood). 2015;240:795–808. doi:10.1177/1535370215584934.
   PubMed Web of Science ®Google Scholar
• Almholt DL, Loechel F, Nielsen SJ, et al. Nuclear export inhibitors and kinase inhibitors identified using a MAPK-activated protein kinase 2 redistribution screen. Assay Drug Dev Technol. 2004;2:7–20. doi:10.1089/154065804322966270.
   PubMed Web of Science ®Google Scholar
• Lundholt BK, Linde V, Loechel F, et al. Identification of Akt pathway inhibitors using redistribution screening on the FLIPR and the IN Cell 3000 analyzer. J Biomol Screen. 2005;10:20–29. doi:10.1177/1087057104269989.
   PubMed Web of Science ®Google Scholar
• Grånäs C, Lundholt BK, Loechel F, et al. Identification of RAS-mitogen-activated protein kinase signaling pathway modulators in an ERF1 redistribution screen. J Biomol Screen. 2006;11:423–434. doi:10.1177/1087057106287136.
   PubMed Web of Science ®Google Scholar
• Nickischer D, Laethem C, Trask OJ Jr, et al. Development and implementation of three mitogen-activated protein kinase (MAPK) signaling pathway imaging assays to provide MAPK module selectivity profiling for kinase inhibitors: MK2-EGFP translocation, c-Jun, and ERK activation. Methods Enzymol. 2006;414:389–418. doi:10.1016/S0076-6879(06)14022-7.
   PubMed Web of Science ®Google Scholar
• Ross S, Chen T, Yu V, et al. High-content screening analysis of the p38 pathway: profiling of structurally related p38alpha kinase inhibitors using cell-based assays. Assay Drug Dev Technol. 2006;4:397–409. doi:10.1089/adt.2006.4.397.
   PubMed Web of Science ®Google Scholar
• Johnston PA, Shinde SN, Hua Y, et al. Development and validation of a high-content screening assay to identify inhibitors of cytoplasmic dynein-mediated transport of glucocorticoid receptor to the nucleus. Assay Drug Dev Technol. 2012;10:432–456. doi:10.1089/adt.2012.456.
   PubMed Web of Science ®Google Scholar
• Michnick SW, MacDonald ML, Westwick JK. Chemical genetic strategies to delineate MAP kinase signaling pathways using protein-fragment complementation assays (PCA). Methods. 2006;40:287–293. doi:10.1016/j.ymeth.2006.07.016.
   PubMed Web of Science ®Google Scholar
• Kumar S, Alibhai D, Margineanu A, et al. FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ. Chemphyschem. 2011;12:609–626. doi:10.1002/cphc.201000874.
   PubMed Web of Science ®Google Scholar
• Halls ML, Poole DP, Ellisdon AM, et al. Detection and quantification of intracellular signaling using FRET-based biosensors and high content imaging. Methods Mol Biol. 2015;1335:131–161. doi:10.1007/978-1-4939-2914-6_10.
   PubMedGoogle Scholar
• Kau TR, Schroeder F, Ramaswamy S, et al. A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. Cancer Cell. 2003;4:463–476.
   PubMed Web of Science ®Google Scholar
• Sutherland JJ, Low J, Blosser W, et al. A robust high-content imaging approach for probing the mechanism of action and phenotypic outcomes of cell-cycle modulators. Mol Cancer Ther. 2011;10:242–254.
   PubMed Web of Science ®Google Scholar
• Cappella P, Gasparri F. Highly multiplexed phenotypic imaging for cell proliferation studies. J Biomol Screen. 2014;19:145–157. doi:10.1177/1087057113495712.
   PubMed Web of Science ®Google Scholar
• Durlak M, Fugazza C, Elangovan S, et al. A novel high-content immunofluorescence assay as a tool to identify at the single cell level γ-globin inducing compounds. PLoS One. 2015;10:e0141083. doi:10.1371/journal.pone.0141083.
   Google Scholar
• Johnston PA, Sen M, Hua Y, et al. HCS campaign to identify selective inhibitors of IL-6-induced STAT3 pathway activation in head and neck cancer cell lines. Assay Drug Dev Technol. 2015;13:356–376. doi:10.1089/adt.2015.663.
   PubMed Web of Science ®Google Scholar
• Kittler R, Pelletier L, Heninger AK, et al. Genome-scale RNAi profiling of cell division in human tissue culture cells. Nat Cell Biol. 2007;9:1401–1412.
   PubMed Web of Science ®Google Scholar
• Gustafsdottir SM, Ljosa V, Sokolnicki KL, et al. Multiplex cytological profiling assay to measure diverse cellular states. PLoS One. 2013;8:e80999. doi:10.1371/journal.pone.0080999.
   PubMed Web of Science ®Google Scholar
• Chan GK, Kleinheinz TL, Peterson D, et al. A simple high-content cell cycle assay reveals frequent discrepancies between cell number and ATP and MTS proliferation assays. PLoS One. 2013;8:e63583. doi:10.1371/journal.pone.0063583.
   PubMed Web of Science ®Google Scholar
• Cappella P, Giansanti V, Pulici M, et al. From “Click” to “Fenton” chemistry for 5-bromo-2ʹ-deoxyuridine determination. Cytometry A. 2013;83:989–1000. doi:10.1002/cyto.a.22343.
   PubMed Web of Science ®Google Scholar
• Murrey HE, Judkins JC, Am Ende CW, et al. Systematic evaluation of bioorthogonal reactions in live cells with clickable halotag ligands: implications for intracellular imaging. J Am Chem Soc. 2015;137:11461–11475. doi:10.1021/jacs.5b06847.
   PubMed Web of Science ®Google Scholar
• Söderberg O, Gullberg M, Jarvius M, et al. Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods. 2006;3:995–1000. doi:10.1038/nmeth947.
   PubMed Web of Science ®Google Scholar
• Sunbul M, Nacheva L, Jäschke A. Proximity-induced covalent labeling of proteins with a reactive fluorophore-binding peptide tag. Bioconjug Chem. 2015;26:1466–1469. doi:10.1021/acs.bioconjchem.5b00304.
   PubMed Web of Science ®Google Scholar
• Los GV, Encell LP, McDougall MG, et al. HaloTag: a novel protein labeling technology for cell imaging and protein analysis. ACS Chem Biol. 2008;3:373–382. doi:10.1021/cb800025k.
   PubMed Web of Science ®Google Scholar
• Kaida A, Sawai N, Sakaguchi K, et al. Fluorescence kinetics in HeLa cells after treatment with cell cycle arrest inducers visualized with Fucci (fluorescent ubiquitination-based cell cycle indicator). Cell Biol Int. 2011;35:359–363. doi:10.1042/CBI20100643.
   PubMed Web of Science ®Google Scholar
• Herce HD, Deng W, Helma J, et al. Visualization and targeted disruption of protein interactions in living cells. Nat Commun. 2013;4:2660. doi:10.1038/ncomms3660.
   PubMed Web of Science ®Google Scholar
• Cautain B, De Pedro N, Murillo Garzón V, et al. High-content screening of natural products reveals novel nuclear export inhibitors. J Biomol Screen. 2014;19:57–65. doi:10.1177/1087057113501389.
   PubMed Web of Science ®Google Scholar
• Dull AB, George AA, Goncharova EI, et al. Identification of compounds by high-content screening that induce cytoplasmic to nuclear localization of a fluorescent estrogen receptor α chimera and exhibit agonist or antagonist activity in vitro. J Biomol Screen. 2014;19:242–252. doi:10.1177/1087057113504136.
   PubMed Web of Science ®Google Scholar
• Neumann B, Walter T, Hériché JK, et al. Phenotypic profiling of the human genome by time-lapse microscopy reveals cell division genes. Nature. 2010;464:721–727.
   PubMed Web of Science ®Google Scholar
• Singh S, Carpenter AE, Genovesio A. Increasing the content of high-content screening: an overview. J Biomol Screen. 2014;19:640–650. doi:10.1177/1087057114528537.
   PubMed Web of Science ®Google Scholar
• Wählby C, Erlandsson F, Bengtsson E, et al. Sequential immunofluorescence staining and image analysis for detection of large numbers of antigens in individual cell nuclei. Cytometry. 2002;47:32–41.
   PubMedGoogle Scholar
• Ma B, Winkelbach S, Lindenmaier W, et al. Six-colour fluorescent imaging of lymphoid tissue based on colour addition theory. Acta Histochem. 2006;108:243–257. doi:10.1016/j.acthis.2006.02.002.
   PubMed Web of Science ®Google Scholar
• Kozak K, Bakos G, Hoff A, et al. Workflow-based software environment for large-scale biological experiments. J Biomol Screen. 2010;15:892–899. doi:10.1177/1087057110377354.
   PubMed Web of Science ®Google Scholar
• Ogier A, Dorval T. HCS-analyzer: open source software for high-content screening data correction and analysis. Bioinformatics. 2012;28:1945–1946. doi:10.1093/bioinformatics/bts288.
   PubMed Web of Science ®Google Scholar
• Stöter M, Niederlein A, Barsacchi R, et al. CellProfiler and KNIME: open source tools for high content screening. Methods Mol Biol. 2013;986:105–122. doi:10.1007/978-1-62703-311-4_8.
   PubMedGoogle Scholar
• Prinz F, Schlange T, Asadullah K. Believe it or not: how much can we rely on published data on potential drug targets? Nat Rev Drug Discov. 2011;10:712. doi:10.1038/nrd3439-c1.
   PubMed Web of Science ®Google Scholar
• Krausz E. High-content siRNA screening. Mol Biosyst. 2007;3:232–240. doi:10.1039/b616187c.
   PubMed Web of Science ®Google Scholar
• Arora S, Beaudry C, Bisanz KM, et al. A high-content RNAi-screening assay to identify modulators of cholesterol accumulation in Niemann-Pick type C cells. Assay Drug Dev Technol. 2010;8:295–320. doi:10.1089/adt.2009.0240.
   PubMed Web of Science ®Google Scholar
• Park KM, Kang E, Jeon YJ, et al. Identification of novel regulators of apoptosis using a high-throughput cell-based screen. Mol Cells. 2007;23:170–174.
   PubMed Web of Science ®Google Scholar
• Trask OJ Jr, Baker A, Williams RG, et al. Assay development and case history of a 32K-biased library high-content MK2-EGFP translocation screen to identify p38 mitogen-activated protein kinase inhibitors on the ArrayScan 3.1 imaging platform. Methods Enzymol. 2006;414:419–439. doi:10.1016/S0076-6879(06)14023-9.
   PubMed Web of Science ®Google Scholar
• Yan J, Zhou H, Kong L, et al. Identification of two novel inhibitors of mTOR signaling pathway based on high content screening. Cancer Chemother Pharmacol. 2013;72:799–808. doi:10.1007/s00280-013-2255-1.
   PubMed Web of Science ®Google Scholar
• Lee JA, Shinn P, Jaken S, et al. Novel phenotypic outcomes identified for a public collection of approved drugs from a publicly accessible panel of assays. PLoS One. 2015;10:e0130796. doi:10.1371/journal.pone.0130796.
   PubMed Web of Science ®Google Scholar
• Hill JA, Szabat M, Hoesli CA, et al. A multi-parameter, high-content, high-throughput screening platform to identify natural compounds that modulate insulin and Pdx1 expression. PLoS One. 2010;5:e12958. doi:10.1371/journal.pone.0012958.
   Google Scholar
• Barabasz A, Foley B, Otto JC, et al. The use of high-content screening for the discovery and characterization of compounds that modulate mitotic index and cell cycle progression by differing mechanisms of action. Assay Drug Dev Technol. 2006;4:153–163. doi:10.1089/adt.2006.4.153.
   PubMed Web of Science ®Google Scholar
• Young DW, Bender A, Hoyt J, et al. Integrating high-content screening and ligand-target prediction to identify mechanism of action. Nat Chem Biol. 2008;4:59–68. doi:10.1038/nchembio.2007.53.
   PubMed Web of Science ®Google Scholar
• Evensen L, Link W, Lorens JB. Image-based high-throughput screening for inhibitors of angiogenesis. Methods Mol Biol. 2013;931:139–151. doi:10.1007/978-1-62703-056-4_8.
   PubMedGoogle Scholar
• Magnaghi P, D’Alessio R, Valsasina B, et al. Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. Nat Chem Biol. 2013;9:548–556. doi:10.1038/nchembio.1313.
   PubMed Web of Science ®Google Scholar
• O’Brien PJ. High-content analysis in toxicology: screening substances for human toxicity potential, elucidating subcellular mechanisms and in vivo use as translational safety biomarkers. Basic Clin Pharmacol Toxicol. 2014;115:4–17. doi:10.1111/bcpt.12227.
   PubMed Web of Science ®Google Scholar
• Su R, Xiong S, Zink D, et al. High-throughput imaging-based nephrotoxicity prediction for xenobiotics with diverse chemical structures. Arch Toxicol. 2015;PMID:26612367. [Epub ahead of print]
   PubMedGoogle Scholar
• Persson M, Løye AF, Mow T, et al. A high content screening assay to predict human drug-induced liver injury during drug discovery. J Pharmacol Toxicol Methods. 2013;68:302–313. doi:10.1016/j.vascn.2013.08.001.
   PubMed Web of Science ®Google Scholar
• Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264.
   PubMed Web of Science ®Google Scholar
• Moffat JG, Rudolph J, Bailey D. Phenotypic screening in cancer drug discovery - past, present and future. Nat Rev Drug Discov. 2014;13:588–602. doi:10.1038/nrd4366.
   PubMed Web of Science ®Google Scholar
• Joy ME, Vollmer LL, Hulkower K, et al. A high-content, multiplexed screen in human breast cancer cells identifies profilin-1 inducers with anti-migratory activities. PLoS One. 2014;9:e88350. doi:10.1371/journal.pone.0088350.
   Google Scholar
• Stoops SL, Pearson AS, Weaver C, et al. Identification and optimization of small molecules that restore E-cadherin expression and reduce invasion in colorectal carcinoma cells. ACS Chem Biol. 2011;6:452–465. doi:10.1021/cb100305h.
   PubMed Web of Science ®Google Scholar
• Chua KN, Sim WJ, Racine V, et al. A cell-based small molecule screening method for identifying inhibitors of epithelial-mesenchymal transition in carcinoma. PLoS One. 2012;7:e33183. doi:10.1371/journal.pone.0033183.
   Google Scholar
• Link W, Oyarzabal J, Serelde BG, et al. Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases. J Biol Chem. 2009;284:28392–28400. doi:10.1074/jbc.M109.038984.
   PubMed Web of Science ®Google Scholar
• Ghosh RN, Grove L, Lapets O. A quantitative cell-based high-content screening assay for the epidermal growth factor receptor-specific activation of mitogen-activated protein kinase. Assay Drug Dev Technol. 2004;2:473–481. doi:10.1089/adt.2004.2.473.
   PubMed Web of Science ®Google Scholar
• Christophe T, Jackson M, Jeon HK, et al. High content screening identifies decaprenyl-phosphoribose 2ʹ epimerase as a target for intracellular antimycobacterial inhibitors. PLoS Pathog. 2009;5:e1000645. doi:10.1371/journal.ppat.1000706.
   PubMed Web of Science ®Google Scholar
• Kim HY, Li X, Jones CT, et al. Development of a multiplex phenotypic cell-based high throughput screening assay to identify novel hepatitis C virus antivirals. Antiviral Res. 2013;99:6–11. doi:10.1016/j.antiviral.2013.04.020.
   PubMed Web of Science ®Google Scholar
• Zych C, Domling A, Ayyavoo V. Development of a robust cell-based high-throughput screening assay to identify targets of HIV-1 viral protein R dimerization. Drug Des Devel Ther. 2013;7:403–412. doi:10.2147/DDDT.S44139.
   PubMed Web of Science ®Google Scholar
• Lucantoni L, Silvestrini F, Signore M, et al. A simple and predictive phenotypic high content imaging assay for Plasmodium falciparum mature gametocytes to identify malaria transmission blocking compounds. Sci Rep. 2015;5:16414.
   Web of Science ®Google Scholar
• De Rycker M, Hallyburton I, Thomas J, et al. Comparison of a high-throughput high-content intracellular Leishmania donovani assay with an axenic amastigote assay. Antimicrob Agents Chemother. 2013;57:2913–2922. doi:10.1128/AAC.02398-12.
   PubMed Web of Science ®Google Scholar
• Brodin P, Christophe T. High-content screening in infectious diseases. Curr Opin Chem Biol. 2011;15:534–539.
   PubMed Web of Science ®Google Scholar
• Kotapalli SS, Nallam SS, Nadella L, et al. Identification of new molecular entities (NMEs) as potential leads against tuberculosis from open source compound repository. PLoS One. 2015;10:e0144018. doi:10.1371/journal.pone.0144018.
   Google Scholar
• Silva-Miranda M, Ekaza E, Breiman A, et al. High-content screening technology combined with a human granuloma model as a new approach to evaluate the activities of drugs against mycobacterium tuberculosis. Antimicrob Agents Chemother. 2015;59:693–697. doi:10.1128/AAC.03705-14.
   PubMed Web of Science ®Google Scholar
• Fuller JA, Shaw GC, Bonnet-Wersinger D, et al. A high content screening approach to identify molecules neuroprotective for photoreceptor cells. Adv Exp Med Biol. 2014;801:773–781. doi:10.1007/978-1-4614-3209-8_97.
   PubMed Web of Science ®Google Scholar
• Rudhard Y, Sengupta Ghosh A, Lippert B, et al. Identification of 12/15-lipoxygenase as a regulator of axon degeneration through high-content screening. J Neurosci. 2015;35:2927–2941. doi:10.1523/JNEUROSCI.2936-14.2015.
   PubMed Web of Science ®Google Scholar
• Rhim JH, Luo X, Xu X, et al. A high-content screen identifies compounds promoting the neuronal differentiation and the midbrain dopamine neuron specification of human neural progenitor cells. Sci Rep. 2015;5:16237. doi:10.1038/srep16237.
   PubMed Web of Science ®Google Scholar
• Whitlon DS, Grover M, Dunne SF, et al. Novel high content screen detects compounds that promote neurite regeneration from cochlear spiral ganglion neurons. Sci Rep. 2015;5:15960. doi:10.1038/srep15960.
   PubMed Web of Science ®Google Scholar
• Giddings AM, Maitra R. A disease-relevant high-content screening assay to identify anti-inflammatory compounds for use in cystic fibrosis. J Biomol Screen. 2010;15:1204–1210. doi:10.1177/1087057110384612.
   PubMed Web of Science ®Google Scholar
• Donato MT, Tolosa L, Jiménez N, et al. High-content imaging technology for the evaluation of drug-induced steatosis using a multiparametric cell-based assay. J Biomol Screen. 2012;17:394–400. doi:10.1177/1087057111427586.
   PubMed Web of Science ®Google Scholar
• Nierobisz LS, Cheatham B, Buehrer BM, et al. High-content screening of human primary muscle satellite cells for new therapies for muscular atrophy/dystrophy. Curr Chem Genom Transl Med. 2013;7:21–29. doi:10.2174/2213988501307010021.
   PubMedGoogle Scholar
• Wani MC, Taylor HL, Wall ME, et al. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc. 1971;93:2325–2327.
   PubMed Web of Science ®Google Scholar
• Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature. 1979;277:665–667.
   PubMed Web of Science ®Google Scholar
• Borel JF, Feurer C, Gubler HU, et al. Biological effects of cyclosporine A: a new antilymphocytic agent. Agents Actions. 1976;6:468–475.
   PubMedGoogle Scholar
• Starzl TE, Klintmalm GB, Porter KA, et al. Liver transplantation with use of cyclosporin a and prednisone. N Engl J Med. 1981;305:266–269. doi:10.1056/NEJM198107303050507.
   PubMed Web of Science ®Google Scholar
• Agarwal RP, McPherson RA, Threatte GA. Evidence of a cyclosporine-binding protein in human erythrocytes. Transplantation. 1986;42:627–632.
   PubMed Web of Science ®Google Scholar
• Pandey R, Botros MA, Nacev BA, et al. Cyclosporin a disrupts notch signaling and vascular lumen maintenance. PLoS One. 2015;10:e0119279. doi:10.1371/journal.pone.0119279.
   Google Scholar
• Somers GF. Pharmacological properties of thalidomide (alpha-phthalimido glutarimide), a new sedative hypnotic drug. Br J Pharmacol Chemother. 1960;15:111–116.
   PubMed Web of Science ®Google Scholar
• Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer. 2004;4:314–322. doi:10.1038/nrc1323.
   PubMed Web of Science ®Google Scholar
• Krönke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343:301–305. doi:10.1126/science.1244851.
   PubMed Web of Science ®Google Scholar
• Gambacorti-Passerini C, Le Coutre P, Mologni L, et al. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis. 1997;23:380–394. doi:10.1006/bcmd.1997.0155.
   PubMed Web of Science ®Google Scholar
• Yamaguchi T, Yoshida T, Kurachi R, et al. Identification of JTP-70902, a p15(INK4b)-inductive compound, as a novel MEK1/2 inhibitor. Cancer Sci. 2007;98:1809–1816. doi:10.1111/j.1349-7006.2007.00604.x.
   PubMed Web of Science ®Google Scholar
• Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–1703. doi:10.1056/NEJMoa1210093.
   PubMed Web of Science ®Google Scholar
• Clay TM, Hobeika AC, Mosca PJ, et al. Assays for monitoring cellular immune responses to active immunotherapy of cancer. Clin Cancer Res. 2001;7:1127–1135.
   PubMed Web of Science ®Google Scholar
• Adams JL, Smothers J, Srinivasan R, et al. Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov. 2015;14(9):603–622.
   PubMed Web of Science ®Google Scholar