8A7I

Crystal structure of BRD9 bromodomain in complex with compound EA-89

Summary for 8A7I

• Entry DOI: 10.2210/pdb8a7i/pdb
• Descriptor: Bromodomain-containing protein 9, ~{N}-[1,1-bis(oxidanylidene)thian-4-yl]-7-[3-methyl-1-(piperidin-4-ylmethyl)indol-5-yl]-4-oxidanylidene-5-propyl-thieno[3,2-c]pyridine-2-carboxamide (3 entities in total)
• Functional Keywords: bromodomain, brd9, inhibitor, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 27321.91

Authors

Faller, M.,Zink, F. (deposition date: 2022-06-21, release date: 2022-08-10, Last modification date: 2024-01-31)

Primary citation

Weisberg, E.,Chowdhury, B.,Meng, C.,Case, A.E.,Ni, W.,Garg, S.,Sattler, M.,Azab, A.K.,Sun, J.,Muz, B.,Sanchez, D.,Toure, A.,Stone, R.M.,Galinsky, I.,Winer, E.,Gleim, S.,Gkountela, S.,Kedves, A.,Harrington, E.,Abrams, T.,Zoller, T.,Vaupel, A.,Manley, P.,Faller, M.,Chung, B.,Chen, X.,Busenhart, P.,Stephan, C.,Calkins, K.,Bonenfant, D.,Thoma, C.R.,Forrester, W.,Griffin, J.D.
BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma.
Blood Cancer J, 12:110-110, 2022

PubMed Abstract: Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interference to assess the dependency on BRD9 in the context of diverse hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) model systems. Following depletion of BRD9 protein, AML cells undergo terminal differentiation, whereas apoptosis was more prominent in ALL and MM. RNA-seq analysis of acute leukemia and MM cells revealed both unique and common signaling pathways affected by BRD9 degradation, with common pathways including those associated with regulation of inflammation, cell adhesion, DNA repair and cell cycle progression. Degradation of BRD9 potentiated the effects of several chemotherapeutic agents and targeted therapies against AML, ALL, and MM. Our findings support further development of therapeutic targeting of BRD9, alone or combined with other agents, as a novel strategy for acute leukemias and MM.

PubMed: 35853853
DOI: 10.1038/s41408-022-00704-7

Experimental method

X-RAY DIFFRACTION (1.76 Å)