Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor

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.

染色质重塑开关/蔗糖非发酵（SWI/SNF）复合物的组分在肿瘤中频发突变，提示该复合物的活性异常在肿瘤发生过程中发挥作用。然而，其各单个亚基在该过程中所扮演的具体角色仍不明确。本研究旨在开发靶向BRD9溴结构域（bromodomain）的抑制剂化合物，以评估其在SWI/SNF复合物中的功能。本文报道了基于新型吡啶酮类骨架的一系列强效且高选择性的BRD9溴结构域抑制剂的发现与开发历程。结合于BRD9的抑制剂的晶体学信息，为本研究优化抑制剂对BRD9的结合效力以及对BRD4的选择性提供了指导。此类化合物可调控BRD9溴结构域的细胞功能，并在急性髓系白血病（AML）异种移植模型中展现出抗肿瘤活性。本研究鉴定出两种化学探针BI-7273（1）与BI-9564（2），二者有望在后续体外（in vitro）与体内（in vivo）环境中进一步探究BRD9溴结构域的生物学功能方面具备实用价值。