Applications of chemogenomic library screening in drug discovery

Key Points A chemogenomic library is a collection of well-defined pharmacological agents. A hit from such a set in a phenotypic screen suggests that the annotated target or targets of the probe molecules are involved in the phenotypic perturbation. The creation and utility of a number of chemogenomic libraries have been described, by academia and industry, and some are commercially available. Chemogenomic screening has the potential to expedite the conversion of phenotypic screening projects into target-based drug discovery approaches. Other applications include drug repositioning, predictive toxicology and the discovery of novel pharmacological modalities. Target identification from phenotypic screening can benefit from the integration of small-molecule chemogenomics with genetic approaches, such as RNA-mediated interference and CRISPR–Cas9. Current limitations of chemogenomic screening include small-molecule polypharmacology, misannotation of biological activity and false-positive results (deriving from compound fluorescence or luciferase reporter binding) for example, although opportunities to overcome these issues, particularly through the incorporation of computational techniques, are emerging. 'Open innovation' and collaborative ventures across academia and industry are required to create and assemble the best pharmacological probes for chemogenomic libraries. Chemogenomic screening is increasingly being applied to expedite the conversion of phenotypic screening projects into target-based drug discovery approaches. Here, Jones and Bunnage discuss the principles of the creation and use of chemogenomic libraries, highlighting key examples and their applications, including target identification, drug repositioning and predictive toxicology. The allure of phenotypic screening, combined with the industry preference for target-based approaches, has prompted the development of innovative chemical biology technologies that facilitate the identification of new therapeutic targets for accelerated drug discovery. A chemogenomic library is a collection of selective small-molecule pharmacological agents, and a hit from such a set in a phenotypic screen suggests that the annotated target or targets of that pharmacological agent may be involved in perturbing the observable phenotype. In this Review, we describe opportunities for chemogenomic screening to considerably expedite the conversion of phenotypic screening projects into target-based drug discovery approache