PDBsum entry 5uvc

Transferase/transferase inhibitor

PDB id: 5uvc

Contents

Protein chain

457 a.a.

Ligands

8PV

SO4 ×2

Waters ×72

PDB id:

5uvc

Name:

Transferase/transferase inhibitor

Title:

Design, synthesis, and evaluation of the first selective and potent g- protein-coupled receptor kinase 2 (grk2) inhibitor for the potential treatment of heart failure

Structure:

Beta-adrenergic receptor kinase 1. Chain: a. Fragment: unp residues 23-538. Synonym: beta-ark-1,g-protein coupled receptor kinase 2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: grk2, adrbk1, bark, bark1. Expressed in: baculovirus expression vector pfastbac1-hm. Expression_system_taxid: 274590

Resolution:

2.65Å R-factor: 0.217 R-free: 0.260

Authors:

I.D.Hoffman,J.D.Lawson

Key ref:

T.Okawa et al. (2017). Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure. J Med Chem, 60, 6942-6990. PubMed id: 28699740 DOI: 10.1021/acs.jmedchem.7b00443

Date:

20-Feb-17 Release date: 26-Jul-17

Protein chain

P25098  (ARBK1_HUMAN) -  Beta-adrenergic receptor kinase 1 from Homo sapiens

Seq: 689 a.a.

Struc: 457 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.15 - [beta-adrenergic-receptor] kinase.
• Reaction: [beta-adrenergic receptor] + ATP = [beta-adrenergic receptor]-phosphate + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acs.jmedchem.7b00443

J Med Chem 60:6942-6990 (2017)

PubMed id: 28699740

Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure.

T.Okawa, Y.Aramaki, M.Yamamoto, T.Kobayashi, S.Fukumoto, Y.Toyoda, T.Henta, A.Hata, S.Ikeda, M.Kaneko, I.D.Hoffman, B.C.Sang, H.Zou, T.Kawamoto.

ABSTRACT

A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC₅₀= 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates β-adrenergic receptor (βAR)-mediated cAMP accumulation and prevents internalization of βARs in β2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeutic for heart failure treatment.