Chemical Probes and Probe Miner recommended in new review in Nature Reviews Genetics
Both the Chemical Probes Portal and the Probe Miner resource have been recommended in an excellent new review in Nature Reviews Genetics on the topic of discovering and validating gene dependencies in cancer cells.
The review is written by Ann Lin and Jason Sheltzer and provides a valuable overview of approaches to investigate genes upon which cancer cells are dependent and that may represent drug targets. It focuses especially on the experimental pitfalls and ways to avoid these, highlighting the problem of ‘poorly validated genetic and pharmacological agents as a common cause of target misidentification’. The main emphasis is on the use of genetic technologies. In addition, it also highlights problems with small molecule perturbants and stresses the importance of resources like the Chemical Probes Portal and Probe Miner that aid researchers in choosing selective small-molecule compounds that are appropriate for use in biological experiments.
Here is a quote from the review:
‘Chemists and chemical biologists have produced several resources to help researchers identify selective small-molecule compounds that are suitable for cancer cell biology. In particular, the Chemical Probes Portal and the Probe Miner resource152 integrate a large number of diverse data sources to offer recommendations (and warnings) concerning the use of compounds to perturb certain proteins. These websites are an excellent initial resource for investigating the potency and specificity of a known compound before embarking on in cellula experiments. For additional information regarding the design and identification of selective chemical compounds, we refer readers to several excellent reviews on these topics.’
The articles referred to in the above paragraph are among the ones that we recommend on the Portal as Key Publications.
The review provides numerous examples of the incorrect identification of genes that are claimed to be essential for the fitness of cancer cells but for which gene knockout has no effect. It also illustrates examples of chemical compounds and even drugs in clinical trial that are claimed to exert their anticancer activity through such non-essential targets but which in fact retain activity even when the target is knocked out genetically – indicating the involvement of ‘off-target effects’.
Lin and Sheltzer’s article should be required reading for any researcher who wishes to avoid experimental pitfalls in the discovery of genes involved in any cellular process or disease mechanism, as well as scientists involved in drug discovery and development. It emphasizes the importance of experimental rigour and especially the selection of well-validated genetic reagents and chemical probes.