Which small molecule? Selecting chemical probes for use in cancer research and target validation

Melanocytes can harbor mutations in oncogenes, including BRAF and NRAS, but not all cells with these mutations display oncogenic competence. In this study, Tagore and colleagues sought to determine if cells within the microenvironment endow oncogenic competence and promote melanoma initiation. Using zebrafish, murine, and human 3D skin reconstruction models, the authors showed that the neurotransmitter GABA is synthesized by melanoma cells and binds to the GABA-A receptor on keratinocytes in the microenvironment, leading to the formation of specialized inhibitory electrochemical cell–cell junctions. GABA blocked the electrical activity between melanoma cells and keratinocytes, and genetic and pharmacologic modulation of GABA signaling enhanced the initiation and growth of melanoma in vivo. Together, these results suggest that communication between melanoma cells and keratinocytes within the microenvironment promotes tumor initiation and that GABAergic signaling may serve as a potential therapeutic target in this disease. For more information, see the article by Tagore and colleagues on page 2270. Artwork by Bianca Dunn.

Source: Cancer Discovery


Small-molecule chemical “probes” complement the use of molecular biology techniques to explore, validate, and generate hypotheses on the function of proteins in diseases such as cancer. Unfortunately, the poor selection and use of small-molecule reagents can lead to incorrect conclusions.

Here, we illustrate examples of poor chemical tools and suggest best practices for the selection, validation, and use of high-quality chemical probes in cancer research. We also note the complexity associated with tools for novel drug modalities, exemplified by protein degraders, and provide advice and resources to facilitate the independent identification of appropriate small-molecule probes by researchers.


Validation of biological targets and pathways will be aided by a shared understanding of the criteria of potency, selectivity, and target engagement associated with small-molecule reagents (“chemical probes”) that enable that work.

Interdisciplinary collaboration between cancer biologists, medicinal chemists, and chemical biologists and the awareness of available resources will reduce misleading data generation and interpretation, strengthen data robustness, and improve productivity in academic and industrial research.

To read the complete research article, go to Cancer Discovery.