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Chemoproteomics Enabled Discovery of Selective Probes for NuA4 Factor BRD8

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posted on 13.09.2021, 14:43 authored by David Remillard, Nikolas A. Savage, Alexia T. Kedves, Joshiawa Paulk, Xin Chen, Francisco J. Garcia, Michael J. Romanowski, Patricia A. Horton, Jason Murphy, Markus Schirle, Edmund M. Harrington, Matthew B. Maxwell, Helen Trinh Pham, Igor Maksimovic, Jason R. Thomas, William C. Forrester
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.