Screening


PHENOTYPIC


SCREENING advancing the science from discovery to regulatory science


Phenotypic screening is transforming drug discovery as advances are made in development of human-based physiologically-relevant in vitro systems. Integration of phenotypic drug discovery approaches with target-based screening can improve success rates as assays can be leveraged for the discovery of novel mechanisms and for building knowledge of disease biology.


By Dr Ellen L. Berg P


harmaceutical productivity continues to stagnate despite advances in genomics, assay technologies and automation that have enabled high throughput screening of millions of compounds in target-based assays. Fewer than 10% of drug discovery programmes entering the clinic make it all the way to regulatory approval. Indeed, in 2016 only 22 novel drugs were approved by the FDA, a six-year low. As the limi- tations of target-based drug discovery (TDD) were becoming apparent earlier this decade, Swinney and Antony1, with their unexpectedly-impactful analysis of historical drug approvals, initiated a shift within the industry to reconsider phenotypic screening approaches or phenotypic drug discovery (PDD) for identifying novel drugs. Despite the challenges with these approaches, phenotypic screening is poised to make an impact.


What is phenotypic screening? Phenotypic screening uses live biological systems (in vitro cell cultures or animal models) and was the primary means employed to discover new drugs prior to the genomics era and large-scale identification of potential drug targets. Target-


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based screening utilises simpler assays, often bio- chemical-based, to identify molecules that interact with a specific protein target and is preferred when the disease biology is well understood and the relevance of a target to that disease has been validated with high confidence, since target-based assays can be run at very high throughput-to- screen multi-million compound libraries. However, as Swinney and Antony1 in their 2011 paper (updated here2 in 2014) observed, despite heavy investment in target discovery and valida- tion, phenotypic approaches have continued to provide a significant fraction of first-in-class drugs. This suggests that although the human genome project was successful in identifying large numbers of prospective drug targets, too few of these have led to new therapies. The methods used to validate these targets (and our knowledge of disease mechanisms) have been inadequate to yield the number of drug approvals needed to sup- port the industry, contributing to the unsustain- able high cost of drugs. Using decision theory analysis of the pharmaceutical R&D process, Scannell and Bosley3 identified ‘predictive validi- ty’ of screening models as a driving factor for


Drug Discovery World Fall 2017


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