7K7Z

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

7K7Z の概要

• エントリーDOI: 10.2210/pdb7k7z/pdb
• 関連するPDBエントリー: 7k7l
• 分子名称: 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, ... (4 entities in total)
• 機能のキーワード: serine/threonine protein kinase, signaling protein, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 118653.23

構造登録者

Spurlino, J.C.,Milligan, C. (登録日: 2020-09-24, 公開日: 2020-10-28, 最終更新日: 2024-04-03)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.60608692764 Å)