High-content phenotypic and pathway profiling to advance drug discovery in diseases of unmet need

Conventional thinking in modern drug discovery postulates that the design of highly selective molecules which act on a single disease-associated target will yield safer and more effective drugs. However, high clinical attrition rates and the lack of progress in developing new effective treatments for many important diseases of unmet therapeutic need challenge this hypothesis. This assumption also impinges upon the efficiency of target agnostic phenotypic drug discovery strategies, where early target deconvolution is seen as a critical step to progress phenotypic hits. In this review we provide an overview of how emerging phenotypic and pathwayprofiling technologies integrate to deconvolute the mechanism-of-action of phenotypic hits. We propose that such in-depth mechanistic profiling may support more efficient phenotypic drug discovery strategies that are designed to more appropriately address complex heterogeneous diseases of unmet need.

Automated summary

Conventional thinking suggests that designing highly selective molecules for single disease-associated targets can lead to safer and more effective drugs, but high clinical attrition rates challenge this assumption. Integration of emerging phenotypic and pathway profiling technologies can help unravel the mechanism-of-action of phenotypic hits, supporting more efficient drug discovery strategies for complex diseases.