Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands.

TitleDegradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands.
Publication TypeJournal Article
Year of Publication2017
AuthorsRemillard, D, Buckley, DL, Paulk, J, Brien, GL, Sonnett, M, Seo, H-S, Dastjerdi, S, Wühr, M, Dhe-Paganon, S, Armstrong, SA, Bradner, JE
JournalAngew Chem Int Ed Engl
Date Published2017 05 15
KeywordsDNA-Binding Proteins, Drug Delivery Systems, Humans, Ligands, Molecular Structure, Nuclear Proteins, Pyrroles, Transcription Factors

<p>The bromodomain-containing protein BRD9, a subunit of the human BAF (SWI/SNF) nucleosome remodeling complex, has emerged as an attractive therapeutic target in cancer. Despite the development of chemical probes targeting the BRD9 bromodomain, there is a limited understanding of BRD9 function beyond acetyl-lysine recognition. We have therefore created the first BRD9-directed chemical degraders, through iterative design and testing of heterobifunctional ligands that bridge the BRD9 bromodomain and the cereblon E3 ubiquitin ligase complex. Degraders of BRD9 exhibit markedly enhanced potency compared to parental ligands (10- to 100-fold). Parallel study of degraders with divergent BRD9-binding chemotypes in models of acute myeloid leukemia resolves bromodomain polypharmacology in this emerging drug class. Together, these findings reveal the tractability of non-BET bromodomain containing proteins to chemical degradation, and highlight lead compound dBRD9 as a tool for the study of BRD9.</p>

Alternate JournalAngew Chem Int Ed Engl
PubMed ID28418626
PubMed Central IDPMC5967236
Grant ListF31 GM116451 / GM / NIGMS NIH HHS / United States
P01 CA066996 / CA / NCI NIH HHS / United States
T32 GM095450 / GM / NIGMS NIH HHS / United States