Development of a new class of potent and highly selective G protein-coupled receptor kinase 5 inhibitors and structural insight from crystal structures of inhibitor complexes

G protein-coupled receptor kinase 5 (GRK5) is an important drug development target for heart failure, cardiac hypertrophy, and cancer. We have designed and developed a new class of highly selective, potent, and non-covalent GRK5 inhibitors. One of the inhibitors displayed GRK5 IC value of 10 nM and...

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Veröffentlicht in:European journal of medicinal chemistry 2024-01, Vol.264, p.115931-115931, Article 115931
Hauptverfasser: Chen, Yueyi, Sonawane, Amol, Manda, Rajesh, Gadi, Ranjith Kumar, Tesmer, John J G, Ghosh, Arun K
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Sprache:eng
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Zusammenfassung:G protein-coupled receptor kinase 5 (GRK5) is an important drug development target for heart failure, cardiac hypertrophy, and cancer. We have designed and developed a new class of highly selective, potent, and non-covalent GRK5 inhibitors. One of the inhibitors displayed GRK5 IC value of 10 nM and exhibited >100,000-fold selectivity over GRK2. The X-ray structure of a ketoamide-derived inhibitor-bound GRK5 showed the formation of a hemithioketal intermediate with active site Cys474 in the GRK5 active site and provided new insights into the ligand-binding site interactions responsible for high selectivity. The current studies serve as an important guide to therapeutic GRK5 inhibitor drug development.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2023.115931