Chemoproteomics Enabled Discovery of Selective Probes for NuA4 Factor BRD8

  • ACS Chem Biol. 2021 Nov 19;16(11):2185-2192. doi: 10.1021/acschembio.1c00256.
David Remillard  1  2 ,  Nikolas A Savage  1 ,  Alexia T Kedves  1 ,  Joshiawa Paulk  1 ,  Xin Chen  1 ,  Francisco J Garcia  1 ,  Michael J Romanowski  1 ,  Patricia A Horton  1 ,  Jason Murphy  1 ,  Markus Schirle  1 ,  Edmund M Harrington  1 ,  Matthew B Maxwell  1 ,  Helen Trinh Pham  1 ,  Igor Maksimovic  1 ,  Jason R Thomas  1 ,  William C Forrester  1
Affiliations
  • 1. Novartis Institutes for BioMedical Research Inc., Cambridge, Massachusetts 02139, United States.
  • 2. Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts 02115, United States.
PMID: 34515462 DOI: 10.1021/acschembio.1c00256
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.

Products