Martin Laetitia J, Koegl Manfred, Bader Gerd, Cockcroft Xiao-Ling, Fedorov Oleg, Fiegen Dennis, Gerstberger Thomas, Hofmann Marco H, Hohmann Anja F, Kessler Dirk, Knapp Stefan, Knesl Petr, Kornigg Stefan, Müller Susanne, Nar Herbert, Rogers Catherine, Rumpel Klaus, Schaaf Otmar, Steurer Steffen, Tallant Cynthia, Vakoc Christopher R, Zeeb Markus, Zoephel Andreas, Pearson Mark, Boehmelt Guido, McConnell Darryl
Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
SGC, University of Oxford , Oxford OX3 7DQ, United Kingdom.
J Med Chem. 2016 May 26;59(10):4462-75. doi: 10.1021/acs.jmedchem.5b01865. Epub 2016 Mar 10.
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/蔗糖非发酵型（SWI/SNF）复合体的组分在肿瘤中经常发生突变，这表明改变该复合体的活性在肿瘤发生过程中起作用。然而，各个亚基在这个过程中所起的作用尚不清楚。我们着手开发一种靶向BRD9溴结构域的抑制剂化合物，以评估其在SWI/SNF复合体中的功能。在此，我们展示了基于一种新型吡啶酮样骨架的强效且选择性的BRD9溴结构域抑制剂系列的发现与开发。与BRD9结合的抑制剂的晶体学信息指导了它们在针对BRD9的效力和对BRD4的选择性方面的开发。这些化合物调节BRD9溴结构域的细胞功能，并在急性髓系白血病异种移植模型中显示出抗肿瘤活性。鉴定出了两种化学探针BI-7273（1）和BI-9564（2），它们在进一步探索体外和体内环境下的BRD9溴结构域生物学方面应该会很有用。
