Elsevier

Drug Discovery Today

Volume 18, Issues 21–22, November 2013, Pages 1067-1073
Drug Discovery Today

Review
Gene to screen
Phenotypic screens as a renewed approach for drug discovery

https://doi.org/10.1016/j.drudis.2013.07.001Get rights and content

Highlights

  • Phenotypic screening is a renewed approach for lead discovery.

  • Phenotypic screen approach may improve the success rate of drug approval.

  • New drug targets can be identified from phenotypic screening of known drug library.

  • Patient derived iPS cells can generate better phenotypic cell-based disease models.

The significant reduction in the number of newly approved drugs in the past decade has been partially attributed to failures in discovery and validation of new targets. Evaluation of recently approved new drugs has revealed that the number of approved drugs discovered through phenotypic screens, an original drug screening paradigm, has exceeded those discovered through the molecular target-based approach. Phenotypic screening is thus gaining new momentum in drug discovery with the hope that this approach may revitalize drug discovery and improve the success rate of drug approval through the discovery of viable lead compounds and identification of novel drug targets.

Section snippets

Molecular target-based screening

The foundation for a molecular target approach of drug development started with advances in pharmacology, as well as synthetic and medicinal chemistry beginning in the early 20th century. The wealth and depth of research performed in the 1950s and 1960s on enzymes and enzyme kinetics provided a method for precise calculation of a compound's potency (IC50 or EC50) and efficacy (% maximal response) of an enzyme [1]. Hundreds of enzymes were discovered and purified during this period, later

Phenotypic screening in drug discovery

Today, the main application of cell-based phenotypic assays is to screen large compound libraries, composed of 0.4–2 million compounds, to identify lead compounds for drug discovery projects. Historically, drug discovery was phenotypic by nature – with new drugs either accidently found, as in case of penicillin, or through designed bactericidal screens to discover additional antibiotics [18]. The phenotypic screening approach for drug discovery is also called ‘forward pharmacology’, ‘classical

Animal-based phenotypic screens

Historically, isolated tissues or animal models were involved in phenotypic screening, as described briefly above. In the past 10–20 years, many disease models of several small animals including Caenorhabditis elegans, zebrafish, Xenopus laevis, and Drosophila melanogaster have been developed and applied to compound screening to achieve relatively high screening throughput [33]. The phenotypic screens using in vivo model systems can provide rich information on compound absorption, distribution,

Cell-based phenotypic assays

With advances in new assay technologies, the throughput of phenotypic screening has greatly improved in the past ten years (Fig. 2). Robotic screening platforms and highly sensitive detection systems have been developed which allow phenotypic assays to be miniaturized and used to rapidly screen large chemical libraries. In contrast to the lack of cellular content of many molecular target-based assays using purified recombinant proteins, cell-based phenotypic assays offer additional biological

Application of primary cells and human cells derived from stem cells

Although recombinant cell lines and immortalized primary cells are commonly used in phenotypic screens to identify lead compounds, largely because they rapidly proliferate and can be expanded for the generation of large quantities of cells needed for HTS, primary human cells and patient derived cells are more desirable for phenotypic screens because of their biological insight and disease relevance. Primary human cells have been used in compound screens that are more biologically relevant for

Phenotypic screening to identify new indications and new targets of approved drugs

The second application of a phenotypic assay is to identify new indications of known drugs – an application that is particularly useful for diseases without an effective therapy. An approved drug collection has recently been established at our center [69] and has been used to identify lead compounds for new applications in different diseases including Giardiasis [20], NF-κB signaling [70], Niemann Pick disease type C [21], Chronic Lymphocytic Leukemia (CLL) [71], Chordoma [72], adrenocortical

Concluding remarks

It has been recognized that there is a genuine need for more biologically relevant screening platforms for drug discovery that may lead to the identification of high quality lead compounds. The new phenotypic screening assays should have great potential to meet this challenge as they are usually much more biologically and/or disease relevant. While the screening throughput and disease relevancy of animal models still needs to be improved, the new cell-based phenotypic screens including those

Acknowledgements

This work was supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health.

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