Call for Manuscripts for ACS Pharmacology & Translational Science Review Series on Recommended Tool Compounds

Biological and pharmacological studies require tool compounds, in addition to knock-out (or knock-down) approaches. Both knock-down and the application of tool compounds are often employed as complementary approaches to study the role of proteins or other target structures. Selective compounds are important tools for basic biological studies as well as for target validation. The ideal, high-quality tool compound requires specific properties,¹⁻⁴ which can differ depending on its application, e.g., in in vitro or in vivo studies. Important properties include (sufficiently) high potency and efficacy, selectivity, stability in the context in which it is applied (e.g., chemical stability at pH 7.4 in an aqueous medium, metabolic stability), sufficiently high water solubility for the route of application (e.g., high water solubility in case of intravenous application or inhalation), suitable pharmacokinetic properties if applied in vivo and depending on the target (e.g., brain permeation for studying brain targets), and low or no toxicity if applied in cellular systems or animal models.

Tool compounds should be characterized as broadly as possible, providing, e.g., affinity, potency, efficacy, solubility, mechanism of action (e.g., covalent or reversible, orthosteric or allosteric), residence time, pharmacokinetic data, and selectivity. However, it is clear that knowledge on potential off-target effects is always limited since investigation of all of the thousands of potential targets is not feasible. Thus, two structurally diverse tool compounds for the same target, or a structurally similar but inactive analog of the tool compound,² can be employed as control compounds. It would be most useful if recommendations on the concentrations or doses that have to be applied for in vitro or in vivo experiments, respectively, could be provided.

Tool compounds can, for example, be agonists, antagonists, inhibitors, positive or negative allosteric modulators, or inhibitors of protein–protein interactions, or they may have other modes of action. They are, according to our definition, not limited to small molecules (also designated “chemical probes”) but include antibodies, nanobodies, aptamers, and other large molecules and biologicals, as well as labeled compounds, e.g., fluorescence-labeled or radiolabeled ligands.

Importantly, it is useful to obtain biological data for tool compounds in different species, not only for human targets but additionally for orthologous targets of mouse and/or rat or other species used as animal models. Nowadays, bioactive compounds are primarily tested on human targets, but then they are utilized in preclinical animal models, sometimes without knowledge on potential species differences. Thus, a specific tool compound should be studied in the relevant species of interest.

The selection of the best tool compounds is not trivial; it is often difficult for a biologist/pharmacologist/translational scientist who may be mainly interested in biological effects rather than the compounds’ properties. Thus, there is an urgent need for a reliable source of such information provided by experts in the field. Fortunately, (still limited) collections of high-quality tool compounds, also provided by some pharmaceutical companies, cheminformatics approaches to identify suitable tool compounds, and databases presenting collections and information on tool compounds have been established and are being expanded.^2,5−7

Medicinal chemists with some knowledge of pharmacology, or interdisciplinary teams of authors, will be perfectly suited to write articles on “Recommended Tool Compounds”, e.g., for a certain target or a target family (for examples, see references (8−10)).

Ideally, the recommended tool compounds should be commercially available or otherwise accessible. If this is not the case, your article may even initiate subsequent commercialization of particular best-in-class tool compounds. Many scientists will be extremely grateful for a resource that will help them to identify and select the best molecular tools for their studies.

We are looking forward to your manuscript. Please contact me if you should wish to discuss whether a specific topic would be suitable for this Review Series.

Views expressed in this editorial are those of the author and not necessarily the views of the ACS.