Development of highly potent and selective GRK5 inhibitors

Abstract

G protein‐coupled receptor kinases (GRKs) regulate cell signaling by triggering receptor desensitization via phosphorylation on G protein‐coupled receptors (GPCRs). (1) 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. (2) 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. An immediate goal is to facilitate the development of more selective inhibitors via rational design by determining x‐ray crystal structures of inhibitor complexes with GRK5. Recently, we have crystallized a hyper‐phosphorylated GRK5, and the active site structure suggested the possibility for compound soaking. Overall, discovery of the inhibitors can significantly facilitate understanding and treatment of cardiovascular diseases and cancer.1. Z. Yang et al., Phosphorylation of G Protein‐Coupled Receptors: From the Barcode Hypothesis to the Flute Model. Molecular Pharmacology 92, 201‐210 (2017).2. L.‐P. Jiang et al., GRK5 functions as an oncogenic factor in non‐small‐cell lung cancer. Cell Death Dis 9, 295 (2018).