Potent and selective GRK2/3 and GRK5/6 inhibitors

Compound 8h and Compound 18 or Compound 19 are highly potent and selective inhibitors of GRK2/3 and GRK5/6, respectively. These compounds are well-tolerated in cellular assays and are considered the gold standard for GRK inhibitors to date. Using these chemical inhibitors produces results similar to those obtained using GRK knockout (KO) cells in phosphorylation and internalization studies. Therefore, Compound 8h (GRK2/3), Compound 18 (GRK5/6), and their combination can be considered an independent, confirmatory approach to evaluating the GRK specificity of agonist-driven GPCR phosphorylation. Moreover, these chemical inhibitors are ideal for elucidating GRK-specific functions in the regulation of endogenous GPCRs in systems where GRK KO is unavailable.