PDBsum entry 5uvc

Transferase/transferase inhibitor

PDB id: 5uvc

Contents

Protein chain

457 a.a.

Ligands

8PV

SO4 ×2

Waters ×72

References listed in PDB file

Key reference

• Title: 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.
• Authors: 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.
• Ref.: J Med Chem, 2017, 60, 6942-6990. [DOI no: 10.1021/acs.jmedchem.7b00443]
• PubMed id: 28699740

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.