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Practical Phenotypic Screening Instruction at SLAS2018

The fundamental determinant of the potential success of a PDD effort is the ability of the screening assay to predict the clinical therapeutic response to a drug with a specific mechanism of action. Nature Reviews Drug Discovery, 16, 531-543 (2017)

By The Lab Man
(AKA SLAS Director of Education Steve Hamilton)

Phenotypic drug discovery (PDD) has been a popular topic at the SLAS International Conference and Exhibition for many years. That popularity led to a 2013 SLAS webinar series, an SLAS special interest group, a special two-part issue of JBS (now SLAS Discovery), and in 2016 the creation of a half-day short course taught by Jonathan Lee (Eli Lilly) and David Swinney (iRND3), “Screening Strategies for Drug Discovery: Matching Tools with Solutions.”  This course was described in SLAS ELN in 2015. Because assays lie at the heart of making PDD effective, for SLAS2018 we are expanding the original Lee and Swinney course with an additional half-day course taught by Fabien Vincent (Pfizer) focused on the practical aspects of phenotypic screening. The new full-day course is called Phenotypic Screening:  Why, When and How.” The Lab Man asked Vincent why there is a continued strong interest in phenotypic assays. He replied with the following points:

  • In the past 25 years, target-based drug discovery has led to notable novel therapies but overall success rates are not at the level once envisioned following the molecular biology and genome sequencing revolutions.
  • There is a very finite number of therapeutic targets with compelling validation data available at any given time. For targets already in the public domain, multiple companies will usually compete for delivering a drug to market, with only the first two or three companies likely getting a return on their R&D investment.
  • Additionally, payer and social pressures are increasing on biotech and pharma companies to deliver truly transformational therapies rather than incremental advances. Such transformational therapies are by definition first-in-class drugs.
  • A review by David Swinney in Nature Reviews Drug Discovery in 2011 revealed that more first-in-class small molecule drugs had come from phenotypic approaches than target-based ones. This was surprising to the pharmaceutical industry as most resources had supported target-based efforts in the previous 20 years.
  • The above factors help explain why phenotypic screening has come back as a serious strategy for drug discovery. As an unbiased (or less biased) approach, it can reveal completely novel biological mechanisms at play in disease, allowing scientists to work on unique targets and develop these novel, first-in-class medicines.

Vincent and colleagues have proposed a “rule of three” guidance for developing predictive phenotypic screens. “In order to interrogate a broad swath of disease-relevant biological space and increase the odds of clinical translation of compounds and mechanisms identified by phenotypic screening, we proposed that assays should strive to mimic the disease of interest as closely as possible in terms of 1) the assay system, 2) the stimulus and 3) in staying close to the clinical end point for the assay readout,” he explains. “This approach minimizes the number of assumptions that are implicitly and explicitly made at project initiation and thus partly mitigates our incomplete understanding of human physiology and disease. Accordingly, phenotypic screening may be considered a more humble way of conducting drug discovery and, with the right assay, one more likely to succeed.”

He points out that the skill sets and experience needed to successfully execute phenotypic assays are quite different from biochemical assays. “Phenotypic assays are minimally cell-based, if not employing organ or whole animal systems. The better ones usually require working with primary cells or iPS cells, sometimes employing 3D or co-culture systems. A number of these technologies are still cutting edge and require a learning curve. Additionally, a deep understanding of the disease is important to select the best system, stimulus and readout for the assay.” It should be noted that SLAS2018 offers several short courses aimed specifically at conveying “how to” information about cellular cultures and assays. 

When discussing common learning curve mistakes, Vincent notes “The most common one a few years ago was developing phenotypic assays that are easily doable but less disease relevant (e.g. reporter assay in a generic cell line). Phenotypic screening is resource intensive and the entire value which can be harvested from this type of project will be derived from the original screening effort, and thus the phenotypic assay. A bad phenotypic assay can thus be worse than no assay as it will consume significant resources while delivering little of interest. Second, screening a set of annotated, biologically active compounds is a great way to pilot a larger screen. It will confirm known mechanisms at play, help inform the hit triage strategy and may lead to novel biology connections. However, no compound is perfectly selective at all concentrations meaning that the annotated targets must be carefully validated rather than taken for granted. Most candidate targets end up being invalid in my experience.“

If you are interested in what’s next with phenotypic screening, Vincent has the following suggestions: 

  • Having access to patient-derived cells and tissue is critically important. Ease of access is improving but still there is much to be done.
  • Technologies enabling the setup of co-culture, 3D systems as well as their interrogation are allowing scientists to more closely mimic whole organs and open up new avenues for biological discoveries.
  • Finally, computational tools allowing the integration of multiple data sources (chemogenomics, proteomics, functional genomics, metabolomics…) enable a comprehensive picture of the disease, the assay and the biology uncovered during the screen to be drawn and mined for novel therapeutic targets.   

Vincent, Lee and Swinney are eager to share their accumulated knowledge about phenotypic screening with you! Consider attending their newly merged course at SLAS2018. There is also a great new companion short course aimed at those responsible for creating and maintaining assay-focused cell cultures: "Set-up and Validation of 3D Primary, Stem Cell and Immortalized Cultures for Downstream Microplate Reader and Imaging Applications."

See you in San Diego!  

About the Author

The Lab Man is SLAS Education Director Steve Hamilton, Ph.D. He is a creative change maker, delivering the fresh thinking and energy that has helped make SLAS the go-to resource for those in life sciences discovery and technology. After years in the drug discovery world, heading many leading-edge automation projects for companies such as Eli Lilly, Scitec and Amgen, Hamilton joined the SLAS professional team in 2010. He received his Ph.D. in analytical chemistry from Purdue University and a B.S. in chemistry from Southeast Missouri State University.

November 6, 2017