5TWX

Crystal Structure of BRD9 bromodomain

Summary for 5TWX

• Entry DOI: 10.2210/pdb5twx/pdb
• Descriptor: Bromodomain-containing protein 9, N-[6-({2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}oxy)hexyl]-2-(4-{2-[N-(1,1-dioxo-1lambda~6~-thian-4-yl)carbamimidoyl]-5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-7-yl}-2-methoxyphenoxy)acetamide (3 entities in total)
• Functional Keywords: bromodomain, inhibitor, chemical degradation, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 58731.82

Authors

Seo, H.-S.,Dhe-Paganon, S. (deposition date: 2016-11-15, release date: 2017-09-27, Last modification date: 2023-10-04)

Primary citation

Remillard, D.,Buckley, D.L.,Paulk, J.,Brien, G.L.,Sonnett, M.,Seo, H.S.,Dastjerdi, S.,Wuhr, M.,Dhe-Paganon, S.,Armstrong, S.A.,Bradner, J.E.
Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands.
Angew. Chem. Int. Ed. Engl., 56:5738-5743, 2017

PubMed Abstract: 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.

PubMed: 28418626
DOI: 10.1002/anie.201611281

Experimental method

X-RAY DIFFRACTION (2.55 Å)