 |
PDBsum entry 4uyh
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transcription
|
PDB id
|
|
|
|
4uyh
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
The discovery of i-Bet726 (gsk1324726a), A potent tetrahydroquinoline apoa1 up-Regulator and selective bet bromodomain inhibitor.
|
|
|
Authors
|
|
R.Gosmini,
V.L.Nguyen,
J.Toum,
C.Simon,
J.M.Brusq,
G.Krysa,
O.Mirguet,
A.M.Riou-Eymard,
E.V.Boursier,
L.Trottet,
P.Bamborough,
H.Clark,
C.W.Chung,
L.Cutler,
E.H.Demont,
R.Kaur,
A.J.Lewis,
M.B.Schilling,
P.E.Soden,
S.Taylor,
A.L.Walker,
M.D.Walker,
R.K.Prinjha,
E.Nicodème.
|
|
|
Ref.
|
|
J Med Chem, 2014,
57,
8111-8131.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Through their function as epigenetic readers of the histone code, the BET family
of bromodomain-containing proteins regulate expression of multiple genes of
therapeutic relevance, including those involved in tumor cell growth and
inflammation. BET bromodomain inhibitors have profound antiproliferative and
anti-inflammatory effects which translate into efficacy in oncology and
inflammation models, and the first compounds have now progressed into clinical
trials. The exciting biology of the BETs has led to great interest in the
discovery of novel inhibitor classes. Here we describe the identification of a
novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and
the optimization into potent compounds active in murine models of septic shock
and neuroblastoma. At the molecular level, these effects are produced by
inhibition of BET bromodomains. X-ray crystallography reveals the interactions
explaining the structure-activity relationships of binding. The resulting lead
molecule, I-BET726, represents a new, potent, and selective class of
tetrahydroquinoline-based BET inhibitors.
|
|
|
|
|
|
|
