6DL2

BRD4 bromodomain 1 in complex with HYB157


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.47 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.198 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

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.

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.

(2018) J Med Chem 61: 6685-6704

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00506
  • Primary Citation of Related Structures:  
    6DL2

  • 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.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4128Homo sapiensMutation(s): 0 
Gene Names: BRD4HUNK1
UniProt & NIH Common Fund Data Resources
Find proteins for O60885 (Homo sapiens)
Explore O60885 
Go to UniProtKB:  O60885
PHAROS:  O60885
GTEx:  ENSG00000141867 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO60885
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GUJ
Query on GUJ

Download Ideal Coordinates CCD File 
B [auth A]3-benzyl-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine
C17 H17 N3 O S
QLGVMPYXPORRCO-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
GUJ Binding MOAD:  6DL2 Ki: 33 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.47 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.198 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.512α = 90
b = 43.13β = 90
c = 79.306γ = 90
Software Package:
Software NamePurpose
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
BUSTERrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-04-17
    Type: Initial release
  • Version 1.1: 2023-10-11
    Changes: Data collection, Database references, Refinement description