6DL2

BRD4 bromodomain 1 in complex with HYB157

6DL2 の概要

• エントリーDOI: 10.2210/pdb6dl2/pdb
• 分子名称: Bromodomain-containing protein 4, 3-benzyl-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: bromodomain, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15526.83

構造登録者

Meagher, J.L.,Stuckey, J.A. (登録日: 2018-05-31, 公開日: 2019-04-17, 最終更新日: 2023-10-11)

主引用文献

Qin, C.,Hu, Y.,Zhou, B.,Fernandez-Salas, E.,Yang, C.Y.,Liu, L.,McEachern, D.,Przybranowski, S.,Wang, M.,Stuckey, J.,Meagher, J.,Bai, L.,Chen, Z.,Lin, M.,Yang, J.,Ziazadeh, D.N.,Xu, F.,Hu, J.,Xiang, W.,Huang, L.,Li, S.,Wen, B.,Sun, D.,Wang, S.
Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression.
J. Med. Chem., 61:6685-6704, 2018

PubMed Abstract: Proteins of the bromodomain and extra-terminal (BET) family are epigenetics "readers" and promising therapeutic targets for cancer and other human diseases. We describe herein a structure-guided design of [1,4]oxazepines as a new class of BET inhibitors and our subsequent design, synthesis, and evaluation of proteolysis-targeting chimeric (PROTAC) small-molecule BET degraders. Our efforts have led to the discovery of extremely potent BET degraders, exemplified by QCA570, which effectively induces degradation of BET proteins and inhibits cell growth in human acute leukemia cell lines even at low picomolar concentrations. QCA570 achieves complete and durable tumor regression in leukemia xenograft models in mice at well-tolerated dose-schedules. QCA570 is the most potent and efficacious BET degrader reported to date.

PubMed: 30019901
DOI: 10.1021/acs.jmedchem.8b00506

実験手法

X-RAY DIFFRACTION (1.47 Å)