A high-content screening platform with fluorescent chemical probes for the discovery of first-in-class therapeutics

2016 ◽  
Vol 52 (47) ◽  
pp. 7433-7445 ◽  
Author(s):  
Ala Jo ◽  
Jinjoo Jung ◽  
Eunha Kim ◽  
Seung Bum Park
Keyword(s):  
Therapeutic Agents ◽  
High Content Screening ◽  
Phenotypic Screening ◽  
Chemical Probes ◽  
Screening Platform

Phenotypic screening as a promising approach to discover novel first-in-class therapeutic agents.

scholarly journals A humanized phenotypic screening platform for chronic pain

2017 ◽  
Vol 14 (6) ◽  
pp. 636-636
Author(s):  
Daniel Tams ◽  
Paul Karila ◽  
Ashley Barnes
Keyword(s):  
Chronic Pain ◽  
Phenotypic Screening ◽  
Screening Platform

Predictive Modeling and Biomechanical Microengineering of Mesenchymal Stem Cells: A High Content Screening Platform to Enhance Lineage Specific Differentiation

2013 ◽  
Author(s):  
Amit Paul ◽  
David Franz ◽  
Sumaira Yahya ◽  
Shan Sun ◽  
Michael Cho
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Predictive Modeling ◽  
Stem Cell Differentiation ◽  
High Content Screening ◽  
Cell Behavior ◽  
Functional Changes ◽  
Screening Platform

Recent evidence suggests that stem cell differentiation can be regulated by modulation of the cell’s biomechanics. The cytoskeletal structures and arrangements in stem cells undergoing differentiation are dramatically altered, and these alterations vary by lineage. The complexity of events associated with the transformation of these precursor cells leaves many questions unanswered about morphological, structural, proteomic, and functional changes in differentiating stem cells. A thorough understanding of stem cell behavior, both experimentally and computationally, would allow for the development of more effective approaches to the expansion of stem cells in vitro and for the regulation of their commitment to a specific phenotype.

scholarly journals From Phenotypic Hit to Chemical Probe: Chemical Biology Approaches to Elucidate Small Molecule Action in Complex Biological Systems

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5702
Author(s):  
Quentin T. L. Pasquer ◽  
Ioannis A. Tsakoumagkos ◽  
Sascha Hoogendoorn
Keyword(s):  
Small Molecules ◽  
Chemical Biology ◽  
Target Identification ◽  
Biologically Active ◽  
Phenotypic Screening ◽  
Biological Processes ◽  
Chemical Probes ◽  
Target Deconvolution ◽  
Cellular Target ◽  
Screening Approaches

Biologically active small molecules have a central role in drug development, and as chemical probes and tool compounds to perturb and elucidate biological processes. Small molecules can be rationally designed for a given target, or a library of molecules can be screened against a target or phenotype of interest. Especially in the case of phenotypic screening approaches, a major challenge is to translate the compound-induced phenotype into a well-defined cellular target and mode of action of the hit compound. There is no “one size fits all” approach, and recent years have seen an increase in available target deconvolution strategies, rooted in organic chemistry, proteomics, and genetics. This review provides an overview of advances in target identification and mechanism of action studies, describes the strengths and weaknesses of the different approaches, and illustrates the need for chemical biologists to integrate and expand the existing tools to increase the probability of evolving screen hits to robust chemical probes.

scholarly journals Increasing the Content of High-Content Screening

2014 ◽  
Vol 19 (5) ◽  
pp. 640-650 ◽  
Author(s):  
Shantanu Singh ◽  
Anne E. Carpenter ◽  
Auguste Genovesio
Keyword(s):  
Data Analysis ◽  
High Throughput Screening ◽  
High Content Screening ◽  
Cell Populations ◽  
Phenotypic Screening ◽  
Data Sets ◽  
Phenotypic Information ◽  
Entire Cell ◽  
Data Analysis Methods ◽  
Screening Approaches

Target-based high-throughput screening (HTS) has recently been critiqued for its relatively poor yield compared to phenotypic screening approaches. One type of phenotypic screening, image-based high-content screening (HCS), has been seen as particularly promising. In this article, we assess whether HCS is as high content as it can be. We analyze HCS publications and find that although the number of HCS experiments published each year continues to grow steadily, the information content lags behind. We find that a majority of high-content screens published so far (60−80%) made use of only one or two image-based features measured from each sample and disregarded the distribution of those features among each cell population. We discuss several potential explanations, focusing on the hypothesis that data analysis traditions are to blame. This includes practical problems related to managing large and multidimensional HCS data sets as well as the adoption of assay quality statistics from HTS to HCS. Both may have led to the simplification or systematic rejection of assays carrying complex and valuable phenotypic information. We predict that advanced data analysis methods that enable full multiparametric data to be harvested for entire cell populations will enable HCS to finally reach its potential.

scholarly journals Compounds enhancing human sperm motility identified using a high-throughput phenotypic screening platform

2021 ◽  
Author(s):  
Franz S. Gruber ◽  
Zoe C. Johnston ◽  
Neil R. Norcross ◽  
Irene Georgiou ◽  
Caroline Wilson ◽  
...  
Keyword(s):  
Sperm Motility ◽  
High Throughput ◽  
Dose Response ◽  
High Throughput Screening ◽  
Human Sperm ◽  
Sperm Function ◽  
Phenotypic Screening ◽  
Enhancing Effect ◽  
Short Period ◽  
Screening Platform

AbstractStudy questionCan a high-throughput screening platform facilitate male fertility drug discovery?Summary answerA high-throughput screening platform identified a large number of compounds that enhanced sperm motility.What is known alreadySeveral efforts to find small molecules modulating sperm function have been performed but not using high-throughput technology.Study design, size, durationHealthy donor semen samples were used and samples were pooled (3-5 donors per pool). Primary screening was performed in singlicate; dose-response screening was performed in duplicate (independent donor pools).Participants/materials, setting, methodsSpermatozoa isolated from healthy donors were prepared by density gradient centrifugation and incubated in 384-well plates with compounds (6.25 uM) to identify those compounds with enhancing effects on motility. A total of ∼17,000 compounds from the following libraries: ReFRAME, Prestwick, Tocris, LOPAC, CLOUD and MMV Pathogen Box were screened. Dose response experiments of screening hits were performed to confirm the enhancing effect on sperm motility. Experiments were performed in a University setting.Main results and the role of chanceFrom our primary single concentration screening, 105 compounds elicited an enhancing effect on sperm motility compared to DMSO treated wells. Confirmed enhancing compounds were grouped based on their annotated targets/target classes. A major target class, phosphodiesterase inhibitors, were identified in particular PDE10A inhibitors as well as number of compounds not previously identified/known to enhance human sperm motility such as those related to GABA signaling.Limitations, reasons for cautionCompounds have been tested with prepared donor spermatozoa and only incubated for a short period of time. Therefore, the effect of compounds on whole semen or with longer incubation time may be different. All experiments were performed in vitro.Wider implications of the findingsThis phenotypic screening assay identified a large number of compounds that increased sperm motility. In addition to furthering our understanding of human sperm function, for example identifying new avenues for discovery, we highlight potential inhibitors as promising start-point for a medicinal chemistry programme for potential enhancement of male infertility. Moreover, with disclosure of the results of screening we present a substantial resource to inform further work in the fieldStudy funding/competing interest(s)This study was supported by the Bill and Melinda Gates Foundation and Scottish Funding Council and Scottish Universities Life Science Alliance.

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