 |
PDBsum entry 5hlp
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transferase/transferase inhibitor
|
PDB id
|
|
|
|
5hlp
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Inhibitors of glycogen synthase kinase 3 with exquisite kinome-Wide selectivity and their functional effects.
|
|
|
Authors
|
|
F.F.Wagner,
J.A.Bishop,
J.P.Gale,
X.Shi,
M.Walk,
J.Ketterman,
D.Patnaik,
D.Barker,
D.Walpita,
A.J.Campbell,
S.Nguyen,
M.Lewis,
L.Ross,
M.Weïwer,
W.F.An,
A.R.Germain,
P.P.Nag,
S.Metkar,
T.Kaya,
S.Dandapani,
D.E.Olson,
A.L.Barbe,
F.Lazzaro,
J.R.Sacher,
J.H.Cheah,
D.Fei,
J.Perez,
B.Munoz,
M.Palmer,
K.Stegmaier,
S.L.Schreiber,
E.Scolnick,
Y.L.Zhang,
S.J.Haggarty,
E.B.Holson,
J.Q.Pan.
|
|
|
Ref.
|
|
Acs Chem Biol, 2016,
11,
1952-1963.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The mood stabilizer lithium, the first-line treatment for bipolar disorder, is
hypothesized to exert its effects through direct inhibition of glycogen synthase
kinase 3 (GSK3) and indirectly by increasing GSK3's inhibitory serine
phosphorylation. GSK3 comprises two highly similar paralogs, GSK3α and GSK3β,
which are key regulatory kinases in the canonical Wnt pathway. GSK3 stands as a
nodal target within this pathway and is an attractive therapeutic target for
multiple indications. Despite being an active field of research for the past 20
years, many GSK3 inhibitors demonstrate either poor to moderate selectivity
versus the broader human kinome or physicochemical properties unsuitable for use
in in vitro systems or in vivo models. A nonconventional analysis of data from a
GSK3β inhibitor high-throughput screening campaign, which excluded known GSK3
inhibitor chemotypes, led to the discovery of a novel
pyrazolo-tetrahydroquinolinone scaffold with unparalleled kinome-wide
selectivity for the GSK3 kinases. Taking advantage of an uncommon tridentate
interaction with the hinge region of GSK3, we developed highly selective and
potent GSK3 inhibitors, BRD1652 and BRD0209, which demonstrated in vivo efficacy
in a dopaminergic signaling paradigm modeling mood-related disorders. These new
chemical probes open the way for exclusive analyses of the function of GSK3
kinases in multiple signaling pathways involved in many prevalent disorders.
|
|
|
|
|
|
|
