TTP Labtech, Phenotypic Screening - 6

PHENOTYPIC SCREENING an e-Book Series Perspective

A Comeback for
Phenotypic Screening
Historically drug discovery was based on
screening compounds that led to desirable changes
in the phenotype of a cell, tissue, or organism.
For a phenotypic screen, the parameters under
investigation would typically include changes in
cell proliferation, health, and morphology.
Although successful, this strategy had several
limitations: the screening assays were often complex
and laborious to set up and run, thereby limiting
the number of compounds that could be screened
in a single campaign. Furthermore, the molecular
mechanism of action of a "hit" compound would
not be known.
As our knowledge of the genes and pathways
involved in diseases increased in the second half
of the 20th century, the phenotypic approach to
screening gradually fell out of favour. Target-based,
in vitro compound screens against specific disease
targets dominated the drug discovery process. Yet
despite the ever increasing ability to carry out larger
high throughput screens against novel targets, the
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success rates of this approach have not matched
expectations. According to Swinney et al., 2011,
target-based assays made up the majority of screens
between 1999 and 20084. However, of the 75
first-in-class drugs approved by the FDA during
this period only 23% were discovered through the
target-based route, whereas 37% were discovered
by phenotypic screening. The lack of in vivo efficacy
of hits from target-based screens was probably due
to the fact that the contribution of a single target to
a disease state was overestimated, especially in the
oncology field. The biology of a cell is complex, with
hundreds of pathways interacting to respond to
external cues in order to maintain a balanced
environment5. So whilst hit compounds may
successfully act on specific targets, this will not
necessarily result in a phenotypic change of the cell.
Similarly, the role of individual targets in multiple
disease states has been underestimated. Several
drugs identified through target-based approaches
were subsequently approved for entirely different
indications than intended. Viagra, for example was
developed to treat hypertension, but infamously

found its use in the treatment of erectile dysfunction.
With the disappointment of drug discovery from
a target-based screening approach there has been a
renewed interest in phenotypic screening as a discovery
tool. Many of the perceived challenges of phenotypic
screening have been overcome by technical advances,
allowing this approach to be adopted more widely.
For example, automated assay and analysis set-ups
have increased screening throughputs to tens, or even
hundreds of thousands of compounds per screen.
More sophisticated storage systems are available
to archive the large amounts of data generated,
although the IT infrastructure to handle the data
effectively can still be limiting. Whereas early phenotypic
screens utilised generic cell lines (e.g. CHO, HEK,
HeLa) for their ease of culture, modern screens have
focussed on more physiological relevant cell lines,
which now include primary cell lines, as well as
induced pluripotentent stem cells (iPS). Together
these have enabled phenotypic screening to become
a realistic option for primary drug screening.
Despite these advances, in the oncology field the
challenge still remains to develop assays that are simple


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TTP Labtech, Phenotypic Screening

Table of Contents for the Digital Edition of TTP Labtech, Phenotypic Screening

Contents
TTP Labtech, Phenotypic Screening - 1
TTP Labtech, Phenotypic Screening - 2
TTP Labtech, Phenotypic Screening - 3
TTP Labtech, Phenotypic Screening - Contents
TTP Labtech, Phenotypic Screening - 5
TTP Labtech, Phenotypic Screening - 6
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