Screening


OPTIMISING PHENOTYPIC SCREENING single-cell analysis versus 3D multicell analysis


In light of the high failure rate of compounds when they are subjected to clinical testing, we are seeing a renaissance in phenotypic screening in drug discovery. However, most phenotypic screening is based on the use of cellular assays and here we debate the advantages and disadvantages of single-cell versus 3D multi-cell analyses.


T


he phenotypic screening of novel drug can- didates determines whether a small molecule (or biologic) exerts the desired


pharmacology, either in vitro (isolated cells, organoids, tissues) or in vivo. This functional approach is ‘unbiased’ given that the molecular tar- get, and therefore molecular mechanism of action (MMOA), is only determined following lead identi- fication and preclinical optimisation. By contrast to phenotypic screening, target-based screening com- mences with a defined MMOA implicated in a spe- cific disease pathology and utilises discrete com- pound libraries designed against this presumed molecular target. In this respect, target-based screen- ing is a ‘biased’ approach. In general, phenotypic screening can identify ‘first-in-class’ compounds against novel targets, while target-based screening is optimal to identify ‘best-in-class’ compounds.


Drug Discovery World Fall 2019 Despite the historical success of phenotypic


screening techniques, target-based screening (often directly measuring the biochemical affinity between chemical compound and the biological target) has predominated compound screening campaigns. This is due to the efficiency of highly-automated and ultra-high throughput biochemical assay systems. By contrast, phenotypic approaches are compara- tively inefficient given the high costs per sample and the low throughput assays frequently employed. Consequently, the approach is usually incompatible with the screening of large compound libraries. This is perhaps ironic, given that unbiased screening (eg phenotypic screening) should arguably be conducted against the broadest compound chemical library possible, with the goal of gaining the broadest range of lead chemical structures. A common feature of both target-based and


By Dr Richard M. Eglen


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