Remillard, David, Savage, Nik, Kedves, Alexia, Paulk, Josh, Chen, Xin, Garcia, Francisco, Romanowski, Michael, Horton, Patricia, Murphy, Jason, Maxwell, Matthew, Pham, Helen, Maksimovic, Igor, Thomas, Jason and Forrester, William (2021) Chemoproteomics Enabled Discovery of Selective Probes for NuA4 Factor BRD8. ACS Chemical Biology.

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 study of ligand engaged complex assemblies, we established a native affinity matrix approach using a functionalized derivative of the BRD9 ligand BI-9564. Unexpectedly, in addition to known interactions with the BRD9 and associated BAF complex proteins, we identify a previously unreported interaction with members of the NuA4 complex through the bromdomain subunit BRD8. We apply this finding, alongside 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 study of BRD9 and BRD8 within respective BAF and NuA4 complexes.

Item Type:	Article
Date Deposited:	28 Sep 2021 00:45
Last Modified:	28 Sep 2021 00:45
URI:	https://oak.novartis.com/id/eprint/43862