6DL2

BRD4 bromodomain 1 in complex with HYB157

Summary for 6DL2

• Entry DOI: 10.2210/pdb6dl2/pdb
• Descriptor: 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)
• Functional Keywords: bromodomain, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15526.83

Authors

Meagher, J.L.,Stuckey, J.A. (deposition date: 2018-05-31, release date: 2019-04-17, Last modification date: 2023-10-11)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.47 Å)