Chemoproteomics Enabled Discovery of Selective Probes for NuA4 Factor BRD8

• Published in: ACS chemical biology Vol. 16; no. 11; pp. 2185 - 2192
• Main Authors: Remillard, David, Savage, Nikolas A, Kedves, Alexia T, Paulk, Joshiawa, Chen, Xin, Garcia, Francisco J, Romanowski, Michael J, Horton, Patricia A, Murphy, Jason, Schirle, Markus, Harrington, Edmund M, Maxwell, Matthew B, Pham, Helen Trinh, Maksimovic, Igor, Thomas, Jason R, Forrester, William C
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 19.11.2021
• Subjects: Benzylamines - pharmacology; Cell Line, Tumor; Cell Lineage; DNA Repair; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - physiology; Humans; Ligands; Models, Molecular; Naphthyridines - pharmacology; Protein Binding; Protein Conformation; Protein Domains; Protein Subunits; Proteomics - methods; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptome
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.1c00256

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.