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Opportunities and Challenges in Phenotypic Drug Discovery: an Industry Perspective

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Opportunities and Challenges in Phenotypic Drug Discovery: an Industry Perspective PERSPECTIVES Nevertheless, there are still challenges in OPINION prospectively understanding the key success factors for modern PDD and how maximal Opportunities and challenges in value can be obtained. Articles published after the analysis by Swinney and Anthony have re-examined the contribution of PDD phenotypic drug discovery: an to new drug discovery6,7 and have refined the conditions for its successful application8. industry perspective Importantly, it is apparent on closer examination that the classification of drugs John G. Moffat, Fabien Vincent, Jonathan A. Lee, Jörg Eder and as ‘phenotypically discovered’ is somewhat Marco Prunotto inconsistent6,7 and that, in fact, the majority of successful drug discovery programmes Abstract | Phenotypic drug discovery (PDD) approaches do not rely on knowledge combine target knowledge and functional of the identity of a specific drug target or a hypothesis about its role in disease, in cellular assays to identify drug candidates contrast to the target-based strategies that have been widely used in the with the most advantageous molecular pharmaceutical industry in the past three decades. However, in recent years, there mechanism of action (MoA). Although there is clear evidence that phenotypic has been a resurgence in interest in PDD approaches based on their potential to screening can be an attractive proposition address the incompletely understood complexity of diseases and their promise for efficiently identifying functionally of delivering first-in-class drugs, as well as major advances in the tools for active hits that lead to first-in-class drugs, cell-based phenotypic screening. Nevertheless, PDD approaches also have the gap between a screening hit and an considerable challenges, such as hit validation and target deconvolution. This efficacious drug is often immense and, in article focuses on the lessons learned by researchers engaged in PDD in the our experience, more challenging than for a hit with a known molecular target. Hopes pharmaceutical industry and considers the impact of ‘omics’ knowledge in for PDD to ‘rescue’ the pharmaceutical defining a cellular disease phenotype in the era of precision medicine, introducing industry might also be viewed as an example the concept of a chain of translatability. We particularly aim to identify features of a Gartner hype cycle, in which a peak of and areas in which PDD can best deliver value to drug discovery portfolios and inflated expectations is followed by a trough can contribute to the identification and the development of novel medicines, of disillusionment, before establishing a plateau of productivity. and to illustrate the challenges and uncertainties that are associated with PDD in This article aims to address two order to help set realistic expectations with regard to its benefits and costs. aspects of this situation: first, to illustrate current challenges and uncertainties that In the past three decades, target-based drug of TDD (for example, see REF. 2), and from are associated with PDD to set realistic discovery (TDD) — in which the starting the authors’ experience and anecdotal expectations for benefits and costs; and point is a defined molecular target that is communications, it seems that efforts within second, to identify areas in which PDD hypothesized to have an important role in the pharmaceutical industry to pursue PDD can best deliver value to drug discovery disease — has been the dominant approach have recently greatly increased compared portfolios through the identification and to drug discovery in the pharmaceutical with the years preceding 2011. The power of the development of novel medicines. In the industry, driven by advances in molecular PDD as a tool to address the complexity past two years, conferences organized by biology and genomics. However, in recent of diseases that are poorly understood by the the New York Academy of Sciences9 and the years, there has been a revival in interest scientific community is also clear (see REF. 3 Keystone Symposia on Molecular in phenotypic drug discovery (PDD) for a recent review). Furthermore, there and Cellular Biology, along with the approaches, which do not rely on knowledge have been recent rapid advances in various establishment of a PDD special interest of the identity of a specific drug target or a technologies for cell-based phenotypic group under the auspices of the Society hypothesis about its role in disease. screening, including the development for Laboratory Automation and Screening, This interest has been catalysed in part of induced pluripotent stem (iPS) cell have sustained discussion around PDD and by an influential analysis by Swinney and technologies4, gene-editing tools such its value for the pharmaceutical industry. Anthony in 2011 that highlighted the strong as CRISPR–Cas5, organoids and imaging This article also aims to capture the spirit contribution of PDD to the discovery of assay technologies. Such tools have enabled of these recent meetings by focusing on first-in-class drugs1. PDD has since been the development of novel cell-based disease the state of the art in PDD, sharing lessons cited by various authors as a potential models that promise to more realistically learned, and carefully examining the solution to the perceived poor productivity recapitulate human disease biology. opportunities and challenges for PDD. NATURE REVIEWS | DRUG DISCOVERY VOLUME 16 | AUGUST 2017 | 531 ©2017 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. PERSPECTIVES We first highlight core concepts in PDD understanding to a mechanistically defined Rare monogenic diseases can also provide and introduce the concept of a chain of effect on a pathway or a biomarker to drug, an opportunity to establish PDD projects translatability for PDD screens, and then and then to a therapeutic effect. with a strong chain of translatability18,19, discuss strategic considerations and as knowledge of the mutation that causes operational aspects for PDD projects, Chain of translatability. The fundamental the disease can be used as the basis for the including library development, hit triage, determinant of the potential success of a development of disease models that are compound optimization and safety PDD effort is the ability of the screening suitable for PDD. For example, pioneering assessments. assay to predict the clinical therapeutic genome-wide expression analysis in patients response to a drug with a specific mechanism with recessive dystrophic epidermolysis Core concepts in PDD of action. This was described by Scannell bullosa (RDEB), a rare disease that is Defining PDD. Drugs typically act by and Bosley as the “predictive validity” of characterized by fragile skin due to mutations engaging a molecular target; however, a discovery model2. Here, we propose the in the COL7A1 gene, showed that the a priori knowledge of that target is term chain of translatability to describe differential expression of genes associated not essential. In the case of PDD, a the presence of a shared mechanistic basis with the transforming growth factor-β ‘physiologically relevant’ biological for the disease model, the assay readout (TGFβ) pathway was responsible for system or cellular signalling pathway is and the biology of the disease in humans, differences in the clinical manifestation of directly interrogated by chemical matter as a framework for developing phenotypic the disease. Based on these results, and the to identify biologically active compounds. screening assays with a greater likelihood of knowledge that the approved angiotensin This target-agnostic approach is the having strong predictive validity. II receptor antagonist losartan attenuates underlying attribute that differentiates PDD projects in the area of infectious both canonical and non-canonical TGFβ PDD from hypothesis-driven TDD10. These disease (seeking antibiotics12, antivirals13 signalling, Nyström et al.20 demonstrated target-agnostic and empirical aspects of and anti-parasitic agents14) often have that long-term losartan treatment of PDD are consistent with its description a strong chain of translatability. Indeed, a COL7A1‑mutant RDEB mice efficiently and usage by scientists in academia and typical PDD assay readout — inhibiting the reduced TGFβ signalling in chronically industry. Use of a uniform definition for replication of bacteria, viruses or parasites injured forepaws and alleviated hallmarks PDD helps to illuminate the impact of PDD on plates — can strongly correspond of RDEB progression. It is possible that on modern drug discovery1,6, and underlines not only to anti-infective activity in a differential phenotypic screen using the importance and impact of empirical in vivo preclinical models, but also to the wild-type and COL7A1‑deficient fibroblasts drug discovery approaches in an era that pharmacodynamic (PD) and the therapeutic could identify compounds that modulate or is dominated by strategies that are based effects sought in patients. For example, that prevent RDEB disease progression to a on molecular target hypotheses1. Although the anti-hepatitis C virus (HCV) drug greater extent than losartan. As in the case primarily an approach for small-molecule daclatasvir was discovered phenotypically of antibacterial and anti-parasitic drugs, discovery, PDD has also contributed to using human cells engineered to express the the chain of translatability for monogenic antibody drug discovery (see the excellent HCV replicon corresponding to a number diseases may extend
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