Nuisance compounds in cellular assays

• Published in: Cell chemical biology Vol. 28; no. 3; pp. 356 - 370
• Main Authors: Dahlin, Jayme L., Auld, Douglas S., Rothenaigner, Ina, Haney, Steve, Sexton, Jonathan Z., Nissink, J. Willem M., Walsh, Jarrod, Lee, Jonathan A., Strelow, John M., Willard, Francis S., Ferrins, Lori, Baell, Jonathan B., Walters, Michael A., Hua, Bruce K., Hadian, Kamyar, Wagner, Bridget K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 18.03.2021
• Subjects: Artificial Intelligence; Biological Products - chemistry; chemical biology; Cheminformatics; drug discovery; high-content screening; high-throughput screening; Humans; interference; nuisance compounds; Pharmaceutical Preparations - chemistry; phenotypic drug discovery; phenotypic screening; nuisance compounds; chemical biology; drug discovery; high-throughput screening; phenotypic screening; interference; phenotypic drug discovery; artifacts; high-content screening
• ISSN: 2451-9456; 2451-9448; 2451-9456
• DOI: 10.1016/j.chembiol.2021.01.021

Compounds that exhibit assay interference or undesirable mechanisms of bioactivity (“nuisance compounds”) are routinely encountered in cellular assays, including phenotypic and high-content screening assays. Much is known regarding compound-dependent assay interferences in cell-free assays. However, despite the essential role of cellular assays in chemical biology and drug discovery, there is considerably less known about nuisance compounds in more complex cell-based assays. In our view, a major obstacle to realizing the full potential of chemical biology will not just be difficult-to-drug targets or even the sheer number of targets, but rather nuisance compounds, due to their ability to waste significant resources and erode scientific trust. In this review, we summarize our collective academic, government, and industry experiences regarding cellular nuisance compounds. We describe assay design strategies to mitigate the impact of nuisance compounds and suggest best practices to efficiently address these compounds in complex biological settings. [Display omitted] Nuisance compounds can waste significant resources by producing promising bioactivities that are attributable to undesirable mechanisms of action. Addressing nuisance compounds is particularly challenging in cellular assays. Dahlin et al. summarize academic, government, and industry experiences with assay design and hit triage to specifically address cellular nuisance compounds.