Recent advances in the development of GRK2 inhibitors: blocking the interaction of GRK2 with its partners.

G protein-coupled receptor kinase 2 (GRK2) is a key player in signal transduction and contains an N-terminus, a kinase domain (KD) and a C-terminus. Changes in the configuration of GRK2 regulate its allosteric effects, including KD closure and protein binding, and the interaction between the KD and the pleckstrin homology (PH) domain modulates the kinase activity of GRK2. GRK2 functions as a central molecule within a complex interactome, interacting with various cytoplasmic or membrane proteins in addition to G-protein coupled receptors (GPCRs), and plays a significant role in several GRK2 dysfunction-related diseases, including arthritis and cardiovascular disorders. Recently, GRK2 inhibitors-including peptide-based inhibitors, RNA aptamers, and small-molecule compounds-have been developed on the basis of targeted blockade of the GRK2-Gαq interface, GRK2-Gβγ interaction, and GRK2 KD-substrate binding, offering hope for the treatment of GRK2 dysfunction-related diseases. However, owing to the unfavourable properties of some small-molecule inhibitors and rapid degradation of peptides, the entry of these GRK2 inhibitors into clinical trials is limited. Understanding the regulation, activity, levels, or specific interactions of GRK2 is crucial for overcoming these challenges and optimizing the clinical use of GRK2 inhibitors. Our current review discusses the structure and function of GRK2, the research progress on GRK2 inhibitors and the regulatory role of GRK2 inhibitors in GRK2 dysfunction-related diseases to provide a significant theoretical basis for extensive research on GRK2-targeted therapies.