Authors:

Phoebe G Smock

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About Paper:

Chronic heart failure and cancer remain among the foremost causes of death worldwide. G protein-coupled receptor kinases 5 and 6 (GRK5 and GRK6) have emerged as critical regulators in the pathophysiology of these diseases, making them promising targets for therapeutic intervention. This study focuses on the discovery and characterization of selective and potent small-molecule inhibitors against GRK5 and GRK6, intending to advance therapeutic strategies for heart failure and multiple myeloma. A series of highly potent and selective inhibitors was synthesized based on Sunitinib, an FDA-approved inhibitor against receptor tyrosine kinases (RTKs), and aminoquinazoline scaffolds. Their kinase activity was quantitatively assessed using radiometric kinase inhibition assays. Moreover, X-ray crystallography was employed to determine the co-crystal structures of GRK5 bound to those drug-like inhibitors, enabling detailed analysis of the binding mode and key molecular interactions within the GRK5 active site. Structural insights into the active site architecture of GRK5 provide a framework for rational optimization of inhibitor selectivity and potency. These findings lay the groundwork for the development of targeted pharmacological agents against GRK5 and GRK6 for the treatment of cardiovascular and cancer- related diseases. Keywords: GRK5 Inhibitors; GRK6 Inhibitors; Sunitinib; Aminoquinazoline; Kinase Inhibition Assays

Source:

Purdue University / 2025

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Co-authors:

Phoebe G Smock