Phenotypic Screening and Target Deconvolution Micro-Credential

Researchers and their organizations will be able to better determine where phenotypic screening could be enabling. They will also be equipped to design and implement robust programs of work to maximize the chances of project success. Learning outputs that will enable this are: 

• Understanding of the principle and concept of phenotypic screening and the key considerations in determining when to choose it as a drug discovery strategy for projects. 
• Knowledge of the key tactics and capabilities in use for phenotypic screening. 
• Awareness of where phenotypic screening has been used successfully including understanding of success factors and risks. 
• Practical application of the knowledge gained during the micro-credential to develop a robust phenotypic drug discovery project proposal.

Section 1: What is Phenotypic Screening and When to Choose It as a Screening Strategy
Objective: Contemporary drug discovery utilizes a spectrum of lead generation approaches ranging from target-directed strategies to phenotypic approaches based on empirical observations. In the past 10 years, there has been a resurgence in the application of phenotypic drug discovery based on its success in delivering first-in-class medicines. In Section 1 we aim to equip you with a detailed understanding of both what is meant by phenotypic screening and when it might be appropriate to consider it as a strategy for drug discovery.  

Learning Outcomes

• Describe the drug discovery and development process
• List the main technical reasons for lack of pharma productivity in recent years
• Compare the pros and cons of target-directed versus phenotypic-based screening strategies
• Evaluate key features of successful phenotypic discovery campaigns and be inspired by how phenotypic discovery is being applied today.

Section 2:  Phenotypic Assay Development and Validation
Objective: Appropriately validated phenotypic assays are a key success criteria for phenotypic programs. In this section 2 we will equip you with a detailed understanding of what an appropriately validated phenotypic assay looks like along with an overview of the latest tools and technologies likely to be most applicable. You will develop an appreciation of the steps involved through a worked example of a high-content assay for a primary phenotypic screen

Learning Outcomes

• What are characteristics of the best assays for phenotypic screening (Rule of 3) 
• Comparison of different cell models (including IPS, cell line, organoid, in vivo)
• Introduction and pros and cons of different screening technologies and endpoints applied to phenotypic assays (including imaging, flow-cytometry, omics, reporter-gene)
• Basic understanding of high-content image analysis with a worked example applied to a phenotypic assay
• Basic understanding of multi-parametric data analysis with a worked example applied to a phenotypic assay
• Understand how next-generation analytics are being employed in phenotypic discovery

Section 3: Phenotypic Screening – Libraries and Technology/Automation Requirements and HIT Triage

Objective: Delivering impact from a phenotypic screen requires appropriate screening library selection and effective selection of hits with the highest likelihood of success in the clinic. In this section we will together explore available perturbation libraries and key considerations in their use as well as outlining key steps involved in hit triage from phenotypic screens.

Learning Outcomes

• Understand factors affecting choice of screening library (type, modality, size): Small molecule libraries, antibody and protein libraries, functional genomic libraries 
• Understand Lab Automation requirements for phenotypic screen
• Describe hit selection and triage strategy for phenotypic projects

Section 4: Target Deconvolution and Mode of Action Elucidation
Objective: It is not essential to understand the molecular target(s) and/or mechanism of action of hits from phenotypic screens but it can be very helpful in assessing the risks of and prioritising programs for preclinical and ultimately clinical development. In this section we will equip you with an understanding of the full range of tools, techniques and approaches that can be used including key considerations on their selection. We will exemplify their use through case studies

Learning Outcomes

• Understand key considerations in designing a target deconvolution strategy from a phenotypic screen
• Understand the main Affinity-based deconvolution methods employed on phenotypic projects
• Understand the main Knowledge-based deconvolution methods employed on phenotypic projects
• Describe the main methods that can be used to validate the molecular target of a phenotypic hit as a therapeutically valid target