6V0S

Crystal structure of the bromodomain of human BRD9 bound to TG003

Summary for 6V0S

• Entry DOI: 10.2210/pdb6v0s/pdb
• Descriptor: Bromodomain-containing protein 9, (1~{Z})-1-(3-ethyl-5-methoxy-1,3-benzothiazol-2-ylidene)propan-2-one (3 entities in total)
• Functional Keywords: brd9, mswi/snf, baf, non-bet, brd, tg003, gene regulation
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 28998.18

Authors

Karim, M.R.,Chan, A.,Schonbrunn, E. (deposition date: 2019-11-19, release date: 2020-03-11, Last modification date: 2023-10-11)

Primary citation

Karim, R.M.,Chan, A.,Zhu, J.Y.,Schonbrunn, E.
Structural Basis of Inhibitor Selectivity in the BRD7/9 Subfamily of Bromodomains.
J.Med.Chem., 63:3227-3237, 2020

PubMed Abstract: Inhibition of the bromodomain containing protein 9 (BRD9) by small molecules is an attractive strategy to target mutated SWI/SNF chromatin-remodeling complexes in cancer. However, reported BRD9 inhibitors also inhibit the closely related bromodomain-containing protein 7 (BRD7), which has different biological functions. The structural basis for differential potency and selectivity of BRD9 inhibitors is largely unknown because of the lack of structural information on BRD7. Here, we biochemically and structurally characterized diverse inhibitors with varying degrees of potency and selectivity for BRD9 over BRD7. Novel cocrystal structures of BRD7 liganded with new and previously reported inhibitors of five different chemical scaffolds were determined alongside BRD9 and BRD4. We also report the discovery of first-in-class dual bromodomain-kinase inhibitors outside the bromodomain and extraterminal family targeting BRD7 and BRD9. Combined, the data provide a new framework for the development of BRD7/9 inhibitors with improved selectivity or additional polypharmacologic properties.

PubMed: 32091206
DOI: 10.1021/acs.jmedchem.9b01980

Experimental method

X-RAY DIFFRACTION (2.4 Å)