Hit Triage and Validation in Phenotypic Screening: Considerations and Strategies. Issue 11 (19th November 2020)

• Record Type: Journal Article
• Authors: Vincent, Fabien; Loria, Paula M.; Weston, Andrea D.; Steppan, Claire M.; Doyonnas, Regis; Wang, Yue-Ming; Rockwell, Kristin L.; Peakman, Marie-Claire
• Is Part Of: Cell chemical biology. Volume 27:Issue 11(2020)
• Page Start: 1332
• Page End: 1346
• Publication Date: 2020-11-19
• Subjects: phenotypic -- screen -- screening funnel -- hit triage -- hit validation -- drug discovery -- mechanism of action -- HTS; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2020.08.009
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: The promise of phenotypic screening resides in its track record of novel biology and first-in-class therapies. However, challenges stemming from major differences between target-based and phenotypic screening do exist. These challenges prompted us to rethink the critical stage of hit triage and validation on the road to clinical candidates and novel drug targets. Whereas this process is usually straightforward for target screening hits, phenotypic screening hits act through a variety of mostly unknown mechanisms within a large and poorly understood biological space. Our analysis suggests successful hit triage and validation is enabled by three types of biological knowledge—known mechanisms, disease biology, and safety—while structure-based hit triage may be counterproductive. Graphical Abstract: Abstract : Phenotypic and target screening have important differences. Vincent et al. conduct an analysis of the hit triage process for phenotypic screens, which suggests successful hit validation and prioritization is best enabled by three types of biological knowledge—known mechanisms, disease biology, and safety—while structure-based hit triage may be counterproductive.