8A7I

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

8A7I の概要

• エントリーDOI: 10.2210/pdb8a7i/pdb
• 分子名称: 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)
• 機能のキーワード: bromodomain, brd9, inhibitor, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 27321.91

構造登録者

Faller, M.,Zink, F. (登録日: 2022-06-21, 公開日: 2022-08-10, 最終更新日: 2024-01-31)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.76 Å)