PerspectiveDrug Discovery

Developing predictive assays: The phenotypic screening “rule of 3”

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Science Translational Medicine  24 Jun 2015:
Vol. 7, Issue 293, pp. 293ps15
DOI: 10.1126/scitranslmed.aab1201

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  • Reply to "Rule of 4- A Novel Approach to Drug Screening"

    We read the e-letter from Knöll and Bauer with great interest, although many of the arguments presented we believe were included in our original manuscript (10.1126/scitranslmed.aab1201).

    For example, we certainly agree that cell-based assays, while useful in many cases, are not a panacea and that “The cellular microenvironment, including the presence of different cell types and a 3D setting, can also provide critical inputs required for the proper development of relevant cellular phenotypes”. Additionally, Table 1 includes the following description for the most desirable biological systems: “Assay system […] aiming to replicate physiology beyond 2D, single cell type systems (e.g., 3D systems, cell co-culture models, cells with physiologically relevant mechanical stimulation)”.

    Again, we also agree with the proposed inclusion of organ- or tissue-derived systems to enable assay readouts more closely related to clinical endpoints, which is why we noted that “focusing on functional, potentially macrophysical (e.g., muscle contraction) readouts reproducing key in vivo disease phenotypes may be more productive […] Indeed, phenotypic screening with functional readouts extends back decades to Sir James Black, who exploited ex vivo assays utilizing contraction of heart tissue to drive the development of beta blockers”.

    The third point made by Knöll and Bauer relates to our Fig. 3, which describes a hypothetical screen and the pathways that could be identified...

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    Competing Interests: Employee of Pfizer, Inc.
  • RE: ”Rule of 4”- A Novel Approach to Drug Screening
    • Ralph Knoll, AstraZeneca, Sweden
    • Other Contributors:
      • Udo Bauer, AstraZeneca, Sweden

    Dear Editor:

    We read with the greatest interest the recent article by Vincent et al., “Developing predictive assays: The phenotypic screening rule of 3” (Science Translational Medicine, 24 June (1)). While we welcome the development of novel strategies to overcome the current productivity crisis in pharmaceutical industry, we do not necessarily agree with all statements made in this interesting article, particularly with regard to cell based phenotypic screens.

    The authors refer to “Generally, phenotypic assays are more physiologically relevant than target-based ones because they are minimally cell-based, if not tissue- or whole-organism–based. Furthermore, they offer the possibility of identifying compounds acting through either unknown targets or unprecedented molecular mechanisms of action (MMOA) for known targets.” Cell based assays may be relevant under certain circumstances such as hematology or cancer biology (among others), where certain cell types play a dominant role, and where consequently cell based phenotypic screens have been successful. However, other phenotypes involve the whole organ, for example in heart failure where, aside from cardiomyocytes, other cell types such as fibroblasts, smooth muscle cells, or endothelial cells play a major role and where significant remodeling processes take place (2). Other complex diseases include for example diabetes, chronic kidney disease, atherosclerosis, auto-immune diseases, just to name a few. While w...

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    Competing Interests: Both authors are employed by AstraZeneca; Dr. Ralph Knoell is also employed by ICMC (Integrated Cardio Metabolic Centre) at Karolinska Institutet.

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