 |
PDBsum entry 4rvr
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transcription
|
PDB id
|
|
|
|
4rvr
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Discovery and characterization of gsk2801, A selective chemical probe for the bromodomains baz2a and baz2b.
|
|
|
Authors
|
|
P.Chen,
A.Chaikuad,
P.Bamborough,
M.Bantscheff,
C.Bountra,
C.W.Chung,
O.Fedorov,
P.Grandi,
D.Jung,
R.Lesniak,
M.Lindon,
S.Müller,
M.Philpott,
R.Prinjha,
C.Rogers,
C.Selenski,
C.Tallant,
T.Werner,
T.M.Willson,
S.Knapp,
D.H.Drewry.
|
|
|
Ref.
|
|
J Med Chem, 2016,
59,
1410-1424.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Abstract
|
|
|
Bromodomains are acetyl-lysine specific protein interaction domains that have
recently emerged as a new target class for the development of inhibitors that
modulate gene transcription. The two closely related bromodomain containing
proteins BAZ2A and BAZ2B constitute the central scaffolding protein of the
nucleolar remodeling complex (NoRC) that regulates the expression of noncoding
RNAs. However, BAZ2 bromodomains have low predicted druggability and so far no
selective inhibitors have been published. Here we report the development of
GSK2801, a potent, selective and cell active acetyl-lysine competitive inhibitor
of BAZ2A and BAZ2B bromodomains as well as the inactive control compound
GSK8573. GSK2801 binds to BAZ2 bromodomains with dissociation constants (KD) of
136 and 257 nM for BAZ2B and BAZ2A, respectively. Crystal structures
demonstrated a canonical acetyl-lysine competitive binding mode. Cellular
activity was demonstrated using fluorescent recovery after photobleaching (FRAP)
monitoring displacement of GFP-BAZ2A from acetylated chromatin. A
pharmacokinetic study in mice showed that GSK2801 had reasonable in vivo
exposure after oral dosing, with modest clearance and reasonable plasma
stability. Thus, GSK2801 represents a versatile tool compound for cellular and
in vivo studies to understand the role of BAZ2 bromodomains in chromatin biology.
|
|
|
|
|
|
|
