G protein‐coupled receptors not currently in the spotlight: free fatty acid receptor 2 and GPR35

摘要

It is widely appreciated that G protein‐coupled receptors have been the most successfully exploited class of targets for the development of small molecule medicines. Despite this, to date, less than 15% of the non‐olfactory G protein‐coupled receptors in the human genome are the targets of a clinically used medicine. In many cases, this is likely to reflect a lack of understanding of the basic underpinning biology of many G protein‐coupled receptors that are not currently in the spotlight, as well as a paucity of pharmacological tool compounds and appropriate animal models to test in vivo function of such G protein‐coupled receptors in both normal physiology and in the context of disease. ‘Open Innovation’ arrangements, in which pharmaceutical companies and public–private partnerships provide wider access to tool compounds identified from ligand screening programmes, alongside enhanced medicinal chemistry support to convert such screening ‘hits’ into useful ‘tool’ compounds will provide important routes to improved understanding. However, in parallel, novel approaches to define and fully appreciate the selectivity and mode of action of such tool compounds, as well as better understanding of potential species orthologue variability in the pharmacology and/or signalling profile of a wide range of currently poorly understood and understudied G protein‐coupled receptors, will be vital to fully exploit the therapeutic potential of this large target class. I consider these themes using as exemplars two G protein‐coupled receptors, free fatty acid receptor 2 and GPR35.