TY - JOUR
AU - McConnell, Darryl
AB - Components of the chromatin remodelling
switch/sucrose nonfermentable (SWI/SNF) complex are recurrently mutated
in tumors, suggesting that altering the activity of the complex plays
a role in oncogenesis. However, the role that the individual subunits
play in this process is not clear. We set out to develop an inhibitor
compound targeting the bromodomain of BRD9 in order to evaluate its
function within the SWI/SNF complex. Here, we present the discovery
and development of a potent and selective BRD9 bromodomain inhibitor
series based on a new pyridinone-like scaffold. Crystallographic information
on the inhibitors bound to BRD9 guided their development with respect
to potency for BRD9 and selectivity against BRD4. These compounds
modulate BRD9 bromodomain cellular function and display antitumor
activity in an AML xenograft model. Two chemical probes, BI-7273 (1) and BI-9564 (2), were
identified that should prove to be useful in further exploring BRD9
bromodomain biology in both in vitro and in vivo settings.
TI - Structure-BasedDesign of an in Vivo Active Selective BRD9 Inhibitor
JF - Journal of Medicinal Chemistry
DO - 10.1021/acs.jmedchem.5b01865
DA - 2016-02-25
UR - https://www.deepdyve.com/lp/pubmed-central/structure-baseddesign-of-an-in-vivo-active-selective-brd9-inhibitor-OSmP2O0vB2
SP - 4462
EP - 4475
VL - 59
IS - 10
DP - DeepDyve
ER -