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Chemoproteomics Enabled Discovery of Selective Probes for NuA4 Factor BRD8
David Remillard1,2, Nikolas A Savage1, Alexia T Kedves1
1Novartis Institutes for BioMedical Research Inc., Cambridge, Massachusetts 02139, United States.
Abstract:
Bromodomain-containing proteins frequently reside in multisubunit chromatin complexes with tissue or cell state-specific compositions. Recent studies have revealed tumor-specific dependencies on the BAF complex bromodomain subunit BRD9 that are a result of recurrent mutations afflicting the structure and composition of associated complex members. To enable the study of ligand engaged complex assemblies, we established a chemoproteomics approach using a functionalized derivative of the BRD9 ligand BI-9564 as an affinity matrix. Unexpectedly, in addition to known interactions with BRD9 and associated BAF complex proteins, we identify a previously unreported interaction with members of the NuA4 complex through the bromodomain-containing subunit BRD8. We apply this finding, alongside a homology-model-guided design, to develop chemical biology approaches for the study of BRD8 inhibition and to arrive at first-in-class selective and cellularly active probes for BRD8. These tools will empower further pharmacological studies of BRD9 and BRD8 within respective BAF and NuA4 complexes.
Insights
Researchers developed a new chemoproteomics method to study chromatin complexes. This approach unexpectedly revealed a novel interaction between BRD8 and the NuA4 complex, leading to the creation of chemical biology tools for studying BRD8 inhibition.
Area of Science:
- Biochemistry
- Molecular Biology
- Chemical Biology
Background:
- Bromodomain-containing proteins are key components of chromatin complexes.
- Tumor-specific dependencies on BRD9 within the BAF complex are linked to mutations.
- Studying ligand-engaged chromatin complexes requires advanced methodologies.
Purpose of the Study:
- To develop a chemoproteomics approach for studying ligand-engaged chromatin complexes.
- To identify novel interactions of bromodomain-containing proteins.
- To create chemical biology tools for investigating BRD8 function and inhibition.
Main Methods:
- Utilized a functionalized BRD9 ligand (BI-9564 derivative) as an affinity matrix for chemoproteomics.
- Applied homology modeling for rational drug design.
- Developed selective and cellularly active chemical probes.
Main Results:
- Established a chemoproteomics method to analyze chromatin complex assemblies.
- Discovered a previously unreported interaction between BRD8 and the NuA4 complex.
- Developed first-in-class chemical biology probes targeting BRD8.
Conclusions:
- The developed chemoproteomics approach is effective for identifying novel protein interactions within chromatin complexes.
- The discovery of the BRD8-NuA4 interaction opens new avenues for research.
- The novel BRD8 probes will facilitate further pharmacological studies of BRD8 and BRD9 in their respective complexes.
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