Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 10, Pages 4462-4475Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01865
Keywords
-
Categories
Funding
- SGC [1097737]
- AbbVie
- Bayer
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Canadian Institutes for Health Research
- Genome Canada
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Takeda
- Wellcome Trust [092809/Z/10/Z]
- Austrian Research Promotion Agency FFG [836644, 842876, 847818]
- Boehringer Ingelheim Fonds Ph.D. Fellowship
- Burroughs-Wellcome Fund
- National Institutes of Health grant [NCI RO1 CA174793]
- Pershing Square Sohn Cancer Research Alliance
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available