Request Demo

Last update 08 May 2025

GRK6

Last update 08 May 2025

Basic Info

Synonyms

G protein-coupled receptor kinase 6, G protein-coupled receptor kinase GRK6, GPRK6

+ [1]

Introduction

Specifically phosphorylates the activated forms of G protein-coupled receptors. Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their desensitization. Seems to be involved in the desensitization of D2-like dopamine receptors in striatum and chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis (By similarity). Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor: LRP6 during Wnt signaling (in vitro).

Drugs associated with GRK6

Novel GRK5/6 inhibitors (Purdue University)

Target

GRK5 x GRK6

Mechanism

GRK5 inhibitors [+1]

Active Org.-

Originator Org.

Purdue University

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

GF-109203X

Target

GRK6 x PKC

Mechanism

GRK6 antagonists [+1]

Active Org.-

Originator Org.

Pfizer Inc.

Active Indication-

Inactive Indication

Inflammation [+2]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GRK6

100 Translational Medicine associated with GRK6

0 Patents (Medical) associated with GRK6

264

Literatures (Medical) associated with GRK6

01 Apr 2025·Computational Biology and Chemistry

Ligand-based cheminformatics and free energy-inspired molecular simulations for prioritizing and optimizing G-protein coupled receptor kinase-6 (GRK6) inhibitors in multiple myeloma treatment

Article

Author: Kar, Supratik ; Ojha, Probir Kumar ; Bhattacharjee, Arnab

Multiple myeloma (MM) is the second most frequently diagnosed hematological malignancy, presenting limited treatment options with no curative potential and significant drug resistance. Recent studies involving genetic knockdown established the crucial role of GRK6 in upholding the viability of MM cells, emphasizing the need to identify potential inhibitors. Computational exploration of GRK6 inhibitors has not been attempted previously. Herein, the present study reports a multilayered lead prioritization and optimization framework using chemometrics and molecular simulations. 2D QSAR studies revealed that hydrogen bonding and polar interactions enhanced GRK6 inhibitory activity, while increased electron accessibility posed a risk of off-target effects. The pharmacophore hypothesis (DDHRRR_1) featured two hydrogen bond donors, one hydrophobic region, and three aromatic rings, laying the foundation for the 3D QSAR models. Hydrophobic groups, such as pyridine and pyrazole, were shown to enhance inhibition, while smaller groups, like ethyl and hydroxyl, reduced activity. 12,557 DrugBank compounds were screened using the developed chemometric models and molecular docking in tandem, which led to the identification of 7 potential parent leads for subsequent QSAR-guided structural optimizations. 350 lead analogs were generated and the top 4 were further analyzed using molecular docking, ADMET, molecular dynamics, and metadynamics analysis based on Principal Component Analysis (PCA), Probability Density Function (PDF), and Free Energy Landscapes (FEL). Upon cumulative retrospection, we propose a novel analog of DB07168 (DB07168-A13) (docking score: -11.2 kcal/mol, MM-GBSA binding energy: -55.2 kcal/mol) as the most promising GRK6 inhibitor, warranting further in vitro validation, for addressing prospective therapeutic intervention in MM.

04 Mar 2025·Biochemistry

Role of the Palmitoyl Group and of the Amphipathic α Helix in the Membrane Binding of the C-Terminus of G-Protein Receptor Kinase 4α/β

Article

Author: Millette, Marc-Antoine ; Coutinho, Ana ; Prieto, Manuel ; Salesse, Christian

Membrane binding of monotopic proteins can involve various post-translational modifications or a combination of some membrane-binding elements. For example, amphipathic α helices and palmitoylation could drive the membrane attachment of proteins. G-protein-coupled receptor kinases (GRKs) regulate the activity of G-protein-coupled receptors. Several members of the family of GRKs are acylated. Moreover, the C-terminus of GRK6 contains an amphipathic α helix and a palmitoyl group, which could also be the case for GRK4 isoforms. In our experiments, GRK4α/β-derived peptides of differing C-terminal lengths (Cter-GRK4α/β variants) were thus studied to discriminate the individual role of the palmitoyl group and amphipathic α helix of Cter-GRK4α/β in its membrane binding. The membrane binding of the Cter-GRK4α/β variants was studied by comparing their maximum insertion pressure (MIP) to lipid monolayers as well as their intrinsic fluorescence properties using large unilamellar vesicles. The MIP data show a higher level of binding of the palmitoylated longest GRK4α/β variant. Moreover, MIP measurements in the absence and presence of 15 mol % of the negatively charged phosphoserine demonstrated that the amphipathic α helix of Cter-GRK4α/β plays a major role in its membrane binding. Accordingly, partition studies of the Cter-GRK4α/β variants to membranes by fluorescence spectroscopy demonstrate the involvement of the palmitoyl group and the amphipathic α helix of the C-terminus of GRK4α/β in its membrane binding. Altogether, the data show that both the palmitoyl group and the amphipathic helix highly favor membrane binding of the C-terminus of GRK4α/β, which should facilitate the proper anchoring of GRK4α/β and phosphorylation of GPCRs.

01 Jan 2025·European Journal of Medicinal Chemistry

Design, synthesis, and X-ray structural studies of a series of highly potent, selective, and drug-like G protein-coupled receptor kinase 5 inhibitors

Article

Author: Gadi, Ranjith Kumar ; Tesmer, John.J.G. ; Gamage, Sandali Piladuwa ; Tesmer, JohnJ G ; Sonawane, Amol ; Chen, Yueyi ; Ghosh, Arun K

G protein-coupled receptor kinase 5 (GRK5) has emerged as a potential drug development target against heart failure and cancer. A close homolog, GRK6 represents a therapeutic target for multiple myeloma. We have rationally designed a series of highly selective, potent, noncovalent, and drug-like GRK5 inhibitors. Several inhibitors exhibited low nanomolar GRK5 inhibition and high selectivity over GRK2, and, surprisingly, some were selective for GRK6. We determined high-resolution X-ray crystal structures of several inhibitors in complex with GRK5, which provide molecular insights into the ligand-binding site interactions responsible for GRK5 selectivity and potency.

Analysis

Perform a panoramic analysis of this field.

view full example data

Hiro LS Researcher

The AI Search Engine Built to Accelerate Biopharma Decisions

Search across billion-scale life sciences data to uncover signals, validate evidence, and act with confidence.

Ask any biopharma research question→

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, Patsnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Discover Synapse Data Servers

Synapse data is now integrated into the PatSnap LS Model Context Protocol (MCP) service. Customize your LLM agent now using our MCP server!

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

GRK6

Basic Info

Related

Analysis