The future of chemical probes is diversity

The scope and mechanisms of chemical tools are expanding rapidly, ranging from different targeting strategies such as covalent reversible and irreversible inhibitors to selective degraders, molecular glues and PROTACs, as well as small molecules targeting non coding RNAs. Never in the history of chemical biology have we experienced such a diversification of pharmaceutical modalities.

Importantly, if these tools are to be used for mechanistic studies, quality criteria for their characterization need to be defined for each of these modalities as the value of a chemical molecule is determined by its annotation and associated data. Yet, while there is increasing awareness in the chemical biology community that well-annotated compounds or compound sets are crucial for linking the effects of these compounds in phenotypic assays to specific targets with some confidence – and guidelines are emerging regarding desirable characterization of these compounds – more broadcasting still needs to be done to reach other communities, including end-users of chemical probes, as well as chemists when annotating their molecules.

The advent of different modalities such as PROTACs, initiated a move from assaying chemical modulators against selective targets and relatively small panels of off-targets, to proteome-wide evaluation of probe molecules. This development was enabled by improvements in proteomics technologies that have also advanced the discovery and characterization of covalent probes and drugs. Degrader characterization also highlighted the need to consider readouts at different concentrations and time points, which will help in interpreting the biological consequences of specific target pharmacology. However, more needs to be done to make these technologies and data accessible in an easy manner for different communities.

International authors from across the globe have contributed to this themed collection of RSC Medicinal Chemistry on chemical probes, providing primary articles, reviews of the literature and an opinion piece on the topic. It is worth pointing out that the diversity of the contributions reflects the broad range of different meanings that researchers associate with the term ‘chemical probe’. This ranges from environmental cellular probes carrying a fluorophore (such as polarity-based probes) to unlabeled inhibitors which can be reversible or covalent, as well as newer modalities, such as molecular glues or degraders. In the imaging community, probes refer to labelled molecules, which may be small molecule or peptide-based. These probes are not necessarily selective or specific, depending on the intended use. In proteomics, a chemical probe often refers to an activity-based probe, which may or may not be specific for a given target. On the other hand, as mentioned above, the chemical biology community has defined criteria for compounds referred to as chemical probes in terms of potency and selectivity. This unfortunate tangle of definitions in the literature contributes to making the right choices for compound characterization more difficult and leads to inappropriate use of compounds in biological experiments and misinterpretation of data.

With this themed collection, we aim to make readers aware of the diversity of meanings for the term “chemical probes” and encourage the community to communicate clearly regarding the appropriate use of well characterized chemical probes.

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