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Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands
David Remillard1, Dennis L Buckley1, Joshiawa Paulk1
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Abstract:
The bromodomain-containing protein BRD9, a subunit of the human BAF (SWI/SNF) nucleosome remodeling complex, has emerged as an attractive therapeutic target in cancer. Despite the development of chemical probes targeting the BRD9 bromodomain, there is a limited understanding of BRD9 function beyond acetyl-lysine recognition. We have therefore created the first BRD9-directed chemical degraders, through iterative design and testing of heterobifunctional ligands that bridge the BRD9 bromodomain and the cereblon E3 ubiquitin ligase complex. Degraders of BRD9 exhibit markedly enhanced potency compared to parental ligands (10- to 100-fold). Parallel study of degraders with divergent BRD9-binding chemotypes in models of acute myeloid leukemia resolves bromodomain polypharmacology in this emerging drug class. Together, these findings reveal the tractability of non-BET bromodomain containing proteins to chemical degradation, and highlight lead compound dBRD9 as a tool for the study of BRD9.
Insights
Researchers developed novel BRD9 chemical degraders, showing significantly higher potency than existing drugs. These degraders offer a new tool for studying BRD9 function and its role in cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- BRD9, a component of the human BAF (SWI/SNF) complex, is a promising cancer therapeutic target.
- Current understanding of BRD9 function is limited, primarily focusing on acetyl-lysine recognition.
- Existing chemical probes target the BRD9 bromodomain, but novel approaches are needed.
Purpose of the Study:
- To create the first BRD9-directed chemical degraders.
- To investigate the efficacy and mechanism of BRD9 chemical degradation.
- To explore the potential of targeting non-BET bromodomains via chemical degradation.
Main Methods:
- Iterative design and synthesis of heterobifunctional ligands.
- Ligands bridge the BRD9 bromodomain and the cereblon E3 ubiquitin ligase complex.
- Testing degraders in acute myeloid leukemia models.
Main Results:
- BRD9 degraders demonstrated 10- to 100-fold enhanced potency compared to parental ligands.
- Divergent chemotypes of BRD9 degraders were studied to resolve bromodomain polypharmacology.
- The lead compound, dBRD9, was identified as a valuable tool for BRD9 research.
Conclusions:
- Non-BET bromodomain-containing proteins are amenable to chemical degradation.
- BRD9 chemical degraders represent a promising new class of anti-cancer therapeutics.
- dBRD9 serves as a crucial tool for advancing the study of BRD9 biology and cancer.