 |
PDBsum entry 5he0
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transferase/transferase inhibitor
|
PDB id
|
|
|
|
5he0
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
621 a.a.
|
|
|
|
|
|
|
|
|
|
|
339 a.a.
|
|
|
|
|
|
|
|
|
|
|
60 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structure-Based design, Synthesis, And biological evaluation of highly selective and potent g protein-Coupled receptor kinase 2 inhibitors.
|
|
|
Authors
|
|
H.V.Waldschmidt,
K.T.Homan,
O.Cruz-Rodríguez,
M.C.Cato,
J.Waninger-Saroni,
K.M.Larimore,
A.Cannavo,
J.Song,
J.Y.Cheung,
P.D.Kirchhoff,
W.J.Koch,
J.J.Tesmer,
S.D.Larsen.
|
|
|
Ref.
|
|
J Med Chem, 2016,
59,
3793-3807.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
G protein-coupled receptors (GPCRs) are central to many physiological processes.
Regulation of this superfamily of receptors is controlled by GPCR kinases
(GRKs), some of which have been implicated in heart failure. GSK180736A,
developed as a Rho-associated coiled-coil kinase 1 (ROCK1) inhibitor, was
identified as an inhibitor of GRK2 and co-crystallized in the active site.
Guided by its binding pose overlaid with the binding pose of a known potent GRK2
inhibitor, Takeda103A, a library of hybrid inhibitors was developed. This
campaign produced several compounds possessing high potency and selectivity for
GRK2 over other GRK subfamilies, PKA, and ROCK1. The most selective compound,
12n (CCG-224406), had an IC50 for GRK2 of 130 nM, >700-fold selectivity over
other GRK subfamilies, and no detectable inhibition of ROCK1. Four of the new
inhibitors were crystallized with GRK2 to give molecular insights into the
binding and kinase selectivity of this class of inhibitors.
|
|
|
|
|
|
|
