G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitors: Current Trends and Future Perspectives

Abstract

G-protein-coupled receptor kinase 2 (GRK2) is a G-protein-coupled receptor kinase that is ubiquitously expressed in many tissues and regulates various intracellular mechanisms. The up- or down-regulation of GRK2 correlates with several pathological disorders. GRK2 plays an important role in the maintenance of heart structure and function; thus, this kinase is involved in many cardiovascular diseases. GRK2 up-regulation can worsen cardiac ischemia; furthermore, increased kinase levels occur during the early stages of heart failure and in hypertensive subjects. GRK2 up-regulation can lead to changes in the insulin signaling cascade, which can translate to insulin resistance. Increased GRK2 levels also correlate with the degree of cognitive impairment that is typically observed in Alzheimer's disease. This article reviews the most potent and selective GRK2 inhibitors that have been developed. We focus on their mechanism of action, inhibition profile, and structure-activity relationships to provide insight into the further development of GRK2 inhibitors as drug candidates.

Impact of paroxetine on proximal β-adrenergic receptor signaling

“…GRK2 activity has increasingly been shown to contribute to the progression of numerous diseases and organ dysfunction 5, 6 . For instance, a large body of work over the last two decades has identified GRK2 as a major regulator of cardiac dysfunction, wherein genetic ablation or inhibition of GRK2 is sufficient to protect the heart from ischemic insult, prevent adverse cardiac remodeling during chronic HF and prevent βAR desensitization to enhance cardiomyocyte contractility 4, 14–17 .…”

“…For instance, a large body of work over the last two decades has identified GRK2 as a major regulator of cardiac dysfunction, wherein genetic ablation or inhibition of GRK2 is sufficient to protect the heart from ischemic insult, prevent adverse cardiac remodeling during chronic HF and prevent βAR desensitization to enhance cardiomyocyte contractility 4, 14–17 . Thus the identification and validation of small molecules inhibitors of GRK2 remains an important priority and has led to the discovery of a number of several types of antagonists, including RNA aptamers, peptides and various small molecules with distinct chemical and structural properties 6 , though generally with poor potency, selectivity or physicochemical properties unfit for therapeutics. However, the Food and Drug Administration-approved SSRI paroxetine was identified using a high throughput aptamer displacement assay to bind directly to GRK2 to inhibit its ability to phosphorylate rhodopsin, tubulin and thyrotropin-releasing hormone receptor, while increasing βAR-stimulated cardiomyocyte (in vitro) and cardiac (in vivo) contractility 7 .…”

“…Upon βAR stimulation, GRK-dependent phosphorylation of the C-terminus of the receptor increases the recruitment of βarrestins (βarr), multifunctional scaffolding proteins that sterically interdict the association between βAR and active G proteins, as well as engage receptor internalization, mechanisms that act to arrest G protein-dependent βAR signaling and desensitize the receptor to prolonged stimulation. Since these classical desensitization mechanisms have been shown to lead to dysfunctional βAR signaling over time, contributing to maladaptive remodeling during heart failure in particular, the development of small molecule inhibitors of GRKs for the study of these processes and as potential therapeutics has been at the forefront of recent research efforts 6 .…”

Noncanonical Roles of G Protein-coupled Receptor Kinases in Cardiovascular Signaling

“…In fact, the role of GRK2 in diverse pathologies including vascular, immune, cancer, and neurological disorders, and methods targeting GRK2 inhibition have been reviewed in detail (99). Recently, a high-throughput screen for small molecule inhibitors of GRK2 was developed using an RNA aptamer to elucidate compounds that would selectively and potently inhibit GRK2 kinase activity (100).…”

“…While it remains to be seen whether these or related compounds will progress through clinical trials to provide a significant advance in the treatment of human HF, these compounds will serve as useful research tools to look at various aspects of GRK2 kinase function in cell culture and animals models of disease. Furthermore, the crystal structure of GRK2 will offer a template on which to not only investigate kinase domain inhibitors, but perhaps target and disrupt protein-protein interactions that represent key aspects of cardiovascular signaling and function or are sources of dysregulation during disease (16, 99, 103). …”