7K7L

Structure of a hit for G Protein Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure

Summary for 7K7L

• Entry DOI: 10.2210/pdb7k7l/pdb
• Descriptor: Beta-adrenergic receptor kinase 1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (5 entities in total)
• Functional Keywords: serine/threonine protein kinase, signaling protein, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 118677.53

Authors

Spurlino, J.C.,Milligan, C. (deposition date: 2020-09-23, release date: 2020-10-28, Last modification date: 2024-04-03)

Primary citation

Xu, G.,Gaul, M.D.,Liu, Z.,DesJarlais, R.L.,Qi, J.,Wang, W.,Krosky, D.,Petrounia, I.,Milligan, C.M.,Hermans, A.,Lu, H.R.,Huang, D.Z.,Xu, J.Z.,Spurlino, J.C.
Hit-to-lead optimization and discovery of a potent, and orally bioavailable G protein coupled receptor kinase 2 (GRK2) inhibitor.
Bioorg.Med.Chem.Lett., 30:127602-127602, 2020

PubMed Abstract: G-protein coupled receptor kinase 2 (GRK2), which is upregulated in the failing heart, appears to play a critical role in heart failure (HF) progression in part because enhanced GRK2 activity promotes dysfunction of β-adrenergic signaling and myocyte death. An orally bioavailable GRK2 inhibitor could offer unique therapeutic outcomes that cannot be attained by current heart failure treatments that directly target GPCRs or angiotensin-converting enzyme. Herein, we describe the discovery of a potent, selective, and orally bioavailable GRK2 inhibitor, 8h, through high-throughput screening, hit-to-lead optimization, structure-based design, molecular modelling, synthesis, and biological evaluation. In the cellular target engagement assays, 8h enhances isoproterenol-mediated cyclic adenosine 3',5'-monophosphate (cAMP) production in HEK293 cells overexpressing GRK2. Compound 8h was further evaluated in a human stem cell-derived cardiomyocyte (HSC-CM) contractility assay and potentiated isoproterenol-induced beating rate in HSC-CMs.

PubMed: 33038544
DOI: 10.1016/j.bmcl.2020.127602

Experimental method

X-RAY DIFFRACTION (2.539 Å)