Small molecule screening by imaging.

Useful small molecule tools can be discovered in imaging screens that measure phenotype in single cells or small organisms. Recent examples include identification of small molecule inhibitors of processes such as cell migration, cytokinesis, mitotic spindle length determination, melanogenesis, aggresome formation, membrane transport and nuclear export. Imaging screens are currently limited by challenges in the areas of image analysis and target identification. We discuss the use of model organisms such as zebrafish in screens and review different methods of target identification. The emerging field of automated image analysis is also introduced.

[1]  Norbert Perrimon,et al.  Parallel Chemical Genetic and Genome-Wide RNAi Screens Identify Cytokinesis Inhibitors and Targets , 2004, PLoS biology.

[2]  Stuart L Schreiber,et al.  Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctation , 2004, Nature Biotechnology.

[3]  Daniel Rauh,et al.  An Unbiased Cell Morphology–Based Screen for New, Biologically Active Small Molecules , 2005, PLoS biology.

[4]  Douglas A. Creager,et al.  The Open Microscopy Environment (OME) Data Model and XML file: open tools for informatics and quantitative analysis in biological imaging , 2005, Genome Biology.

[5]  Young-Tae Chang,et al.  Dissection of melanogenesis with small molecules identifies prohibitin as a regulator. , 2005, Chemistry & biology.

[6]  Marc Vidal,et al.  Predictive models of molecular machines involved in Caenorhabditis elegans early embryogenesis , 2005, Nature.

[7]  Timothy J Mitchison,et al.  Screening for cell migration inhibitors via automated microscopy reveals a Rho-kinase inhibitor. , 2005, Chemistry & biology.

[8]  Wolfgang Rottbauer,et al.  High-throughput assay for small molecules that modulate zebrafish embryonic heart rate , 2005, Nature chemical biology.

[9]  Sebastian A. Leidel,et al.  Functional genomic analysis of cell division in C. elegans using RNAi of genes on chromosome III , 2000, Nature.

[10]  L. Zon,et al.  In vivo drug discovery in the zebrafish , 2005, Nature Reviews Drug Discovery.

[11]  Pamela A. Silver,et al.  A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. , 2003, Cancer cell.

[12]  Lani F. Wu,et al.  Multidimensional Drug Profiling By Automated Microscopy , 2004, Science.

[13]  Norbert Perrimon,et al.  Genome-wide high-throughput screens in functional genomics. , 2004, Current opinion in genetics & development.

[14]  B. Stockwell,et al.  Biological mechanism profiling using an annotated compound library. , 2003, Chemistry & biology.

[15]  Mark Stamnes,et al.  Secramine inhibits Cdc42-dependent functions in cells and Cdc42 activation in vitro , 2006, Nature chemical biology.

[16]  Tae-Wook Kang,et al.  A novel microtubule destabilizing entity from orthogonal synthesis of triazine library and zebrafish embryo screening. , 2002, Journal of the American Chemical Society.

[17]  Brent R Stockwell,et al.  Advances in chemical genetics. , 2005, Annual review of genomics and human genetics.

[18]  Yann LeCun,et al.  Toward automatic phenotyping of developing embryos from videos , 2005, IEEE Transactions on Image Processing.

[19]  Randall W King,et al.  Small molecules that delay S phase suppress a zebrafish bmyb mutant , 2005, Nature chemical biology.

[20]  Robert F Murphy,et al.  From quantitative microscopy to automated image understanding. , 2004, Journal of biomedical optics.

[21]  Petra Ross-Macdonald,et al.  Model systems in drug discovery: chemical genetics meets genomics. , 2003, Pharmacology & therapeutics.

[22]  Timothy J Mitchison,et al.  A Novel Action of Histone Deacetylase Inhibitors in a Protein Aggresome Disease Model , 2004, Current Biology.

[23]  J. Dowling,et al.  Small molecule developmental screens reveal the logic and timing of vertebrate development. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[24]  D. L. Taylor,et al.  High content screening applied to large-scale cell biology. , 2004, Trends in biotechnology.

[25]  Timothy J Mitchison,et al.  High‐Content Screening and Profiling of Drug Activity in an Automated Centrosome‐Duplication Assay , 2005, Chembiochem : a European journal of chemical biology.

[26]  P. Zipperlen,et al.  Functional genomic analysis of C. elegans chromosome I by systematic RNA interference , 2000, Nature.

[27]  T. Mitchison,et al.  Phenotypic screening of small molecule libraries by high throughput cell imaging. , 2003, Combinatorial chemistry & high throughput screening.

[28]  P. Schultz,et al.  Identification of a novel protein regulating microtubule stability through a chemical approach. , 2004, Chemistry & biology.

[29]  T. Mitchison,et al.  Small molecules in an RNAi world. , 2006, Molecular bioSystems.

[30]  David R Spring,et al.  Chemical genetics to chemical genomics: small molecules offer big insights. , 2005, Chemical Society reviews.

[31]  A. Coulson,et al.  Full-genome RNAi profiling of early embryogenesis in Caenorhabditis elegans , 2005, Nature.

[32]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Erik Brauner,et al.  Informatics and Quantitative Analysis in Biological Imaging , 2003, Science.

[34]  Timothy J Mitchison,et al.  Small‐Molecule Screening and Profiling by Using Automated Microscopy , 2005, Chembiochem : a European journal of chemical biology.

[35]  Peter Wipf,et al.  Cell-active dual specificity phosphatase inhibitors identified by high-content screening. , 2003, Chemistry & biology.