LAUSR

Adhesion G protein-coupled receptors (aGPCRs) — one of the five main families in the GPCR superfamily — have several atypical characteristics, including large, multi-domain N termini and a highly conserved region that can be autoproteolytically cleaved. Although GPCRs overall have well-established pharmacological tractability, currently no therapies that target any of the 33 members of the aGPCR family are either approved or in clinical trials. However, human genetics and preclinical research have strengthened the links between aGPCRs and disease in recent years. This, together with a greater understanding of their functional complexity, has led to growing interest in aGPCRs as drug targets. A framework for prioritizing aGPCR targets and supporting approaches to develop aGPCR modulators could therefore be valuable in harnessing the untapped therapeutic potential of this family. With this in mind, here we discuss the unique opportunities and challenges for drug discovery in modulating aGPCR functions, including target identification, target validation, assay development and safety considerations, using ADGRG1 as an illustrative example.Adhesion G protein-coupled receptors (aGPCRs) have been linked to multiple diseases, but no therapeutics targeting this GPCR family are yet in clinical trials, in part because a lack of understanding of the atypical features of aGPCRs has hampered the development of molecules targeting them. In this Perspective, Bassilana and colleagues discuss how recent advances in aGPCR biology could provide the basis for a framework to approach the unique challenges of drug discovery programmes targeting these receptors.