Therapeutic targeting of adhesion GPCRs: a status update and future potential

Adhesion G-Protein Coupled Receptors (aGPCRs) represent the second largest GPCR family and consist of 32 members in humans, of which 19 are orphan receptors. Despite making up a substantial portion of GPCRs, there are no clinically approved therapeutics targeting them or using them in clinical applications. aGPCRs have functional roles in numerous tissues and their dysregulation through mutations or expression is associated with a variety of diseases, including cancer. Therefore, there is strong interest in therapeutic targeting aGPCRs or their controlled pathways.

The authors showcase the currently available approaches (small molecules, antibodies, knockouts/downs, peptides, nanoparticles, and cell-based therapies) that modulate aGPCR function or pathways. Furthermore, the authors discuss aGPCRs with potential for future therapeutic targeting. Of all aGPCRs, 14 are being exploited as targets and 7 have potential. For the remaining 11, a brief description of their function and any known involvement in disease were included.

The field is currently hampered by lack of knowledge about endogenous ligands and downstream signaling for aGPCRs. Once this knowledge gap is overcome, a clear library of agonists and antagonists can be developed, unleashing successful and widespread aGPCR exploitation and modulation. In the coming years, ligand identification will accelerate, allowing more aGPCR therapeutic advances.