Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology

Abstract

Small-molecule chemical probes or tools have become progressively more important in recent years as valuable reagents to investigate fundamental biological mechanisms and processes causing disease, including cancer. Chemical probes have also achieved greater prominence alongside complementary biological reagents for target validation in drug discovery. However, there is evidence of widespread continuing misuse and promulgation of poor-quality and insufficiently selective chemical probes, perpetuating a worrisome and misleading pollution of the scientific literature. We discuss current challenges with the selection and use of chemical probes, and suggest how biologists can and should be more discriminating in the probes they employ.

Targeting the Small GTPase Superfamily through Their Regulatory Proteins

“…Some of the papers in this review formed conclusions based on a single unvalidated compound. In the worst‐case scenario, it results in a target misidentified in a disease, leading researchers on a wild goose chase, and to the therapeutic strategy of targeting GTPases and their regulators being incorrectly judged to be fruitless …”

“…The majority of small molecules described in this review are better described as chemical‐probe leads rather than validated chemical probes and require additional optimization and characterization before they can be used in cellular assays to provide a robust link between phenotype and target. Molecules that meet chemical probe criteria as described by Arrowsmith et al .…”

Targeting der kleinen GTPasen über ihre regulatorischen Proteine

“…Im schlimmsten Fall führt dies zu einer Fehlidentifizierung der Zielstruktur bei einer Erkrankung. Forscher begeben sich so auf eine sinnlose Suche und die therapeutische Strategie, auf GTPasen und ihre Regulatoren abzuzielen, wird fälschlicherweise als aussichtslos beurteilt …”

The proteostasis network provides targets for neurodegeneration

“…Potential limitations of the tool compounds selected are highlighted in Table 1, where-in the authors' opinion-a compound lacks sufficient published evidence to be considered a "fit-for-purpose" tool or contains a substructure of known pan-assay interference compounds. For further insight into what constitutes a "fit-for-purpose" chemical tool, readers are directed to an excellent recent perspective by Blagg and Workman (2017).…”