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）复合体的组分在肿瘤中频发突变，提示改变该复合体的活性在肿瘤发生过程中发挥了重要作用。然而，各单个亚基在此过程中所扮演的角色仍不明确。本研究旨在开发一种靶向BRD9溴结构域（bromodomain）的抑制剂化合物，以评估其在SWI/SNF复合体中的功能。本文报道了基于新型吡啶酮类支架的强效且选择性BRD9溴结构域抑制剂系列的发现与开发工作。与BRD9结合的抑制剂的晶体学信息，为优化该类化合物对BRD9的效力以及对BRD4的选择性提供了指导依据。这些化合物可调控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。最终鉴定出两种化学探针BI-7273（1）与BI-9564（2），其有望在体外（in vitro）和体内（in vivo）环境中进一步探究BRD9溴结构域的生物学功能。