Development of highly potent and selective inhibitors for GRK5

Abstract

<b>Abstract ID 14062</b> <b>Poster Board 153</b> G protein-coupled receptor kinases (GRKs) regulate cell signaling by triggering receptor desensitization via phosphorylation on G protein-coupled receptors (GPCRs). The seven human GRKs (GRK1−GRK7) are classified into three subfamilies: GRK1 (GRK1 and GRK7), GRK2 (GRK2 and GRK3), and GRK4 (GRK4, GRK5, and GRK6). GRK2 and GRK5 are the most abundant in cardiovascular tissue, where they are potential targets for treatment of cardiovascular disease. GRK5 also undergoes Ca²⁺/calmodulin-dependent nuclear localization, where it phosphorylates histone deacetylase 5 (HDAC5), inducing an increase in transcription of cardiac hypertrophy-related genes. In GRK5-knockdown mice, cardiomyocytes are protected from hypertrophy; however, the specific roles of GRK5 in heart failure and hypertrophic cardiomyopathy are still unclear. Furthermore, GRK5 is required for cancer progression in various cancer types. Depletion of GRK5 has been shown to suppress prostate cancer, breast cancer, and non-small-cell lung cancer. Therefore, targeting GRK5 can also be a chemotherapeutic strategy. Here we are testing a series of inhibitors for GRK5/6 derived from the indolinone scaffold, utilizing Cys474 residue unique in GRK5/6 to enhance selectivity by covalent capture. We have been exploring different inhibitor warheads for improving potency and selectivity without potentially toxic functional groups. So far, we have identified several highly potent and selective GRK5 inhibitors. We are also in the progress of solving the co-crystal structure of GRK5 with the inhibitors for a better understanding of the inhibition mechanisms and facilitating improvement of inhibitors. Recently, we have also resolved the structure of an apo-GRK5, which will greatly enhance our understanding of the enzymatic mechanisms of GRK5 and improve the chance for ligand soaking. Overall, discovery of the inhibitors can significantly facilitate understanding and treatment of cardiovascular diseases and cancers.