5KTW

CREBBP bromodomain in complex with Cpd 44 (3-((5-acetyl-1-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-isopropylbenzamide)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.09 Å
  • R-Value Free: 0.176 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.163 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300.

Crawford, T.D.Romero, F.A.Lai, K.W.Tsui, V.Taylor, A.M.de Leon Boenig, G.Noland, C.L.Murray, J.Ly, J.Choo, E.F.Hunsaker, T.L.Chan, E.W.Merchant, M.Kharbanda, S.Gascoigne, K.E.Kaufman, S.Beresini, M.H.Liao, J.Liu, W.Chen, K.X.Chen, Z.Conery, A.R.Cote, A.Jayaram, H.Jiang, Y.Kiefer, J.R.Kleinheinz, T.Li, Y.Maher, J.Pardo, E.Poy, F.Spillane, K.L.Wang, F.Wang, J.Wei, X.Xu, Z.Xu, Z.Yen, I.Zawadzke, L.Zhu, X.Bellon, S.Cummings, R.Cochran, A.G.Albrecht, B.K.Magnuson, S.

(2016) J Med Chem 59: 10549-10563

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01022
  • Primary Citation of Related Structures:  
    5KTU, 5KTW, 5KTX, 5KU3

  • PubMed Abstract: 

    The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC 50 = 0.02 μM, BRET IC 50 = 0.41 μM, BRD4(1) IC 50 = 13 μM) that retained the best balance of cell potency, selectivity, and in vivo PK. Compound 59 showed a marked antiproliferative effect in hematologic cancer cell lines and modulates MYC expression in vivo that corresponds with antitumor activity in an AML tumor model.


  • Organizational Affiliation

    Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CREB-binding protein
A, B, C
114Homo sapiensMutation(s): 0 
Gene Names: CREBBPCBP
EC: 2.3.1.48
UniProt & NIH Common Fund Data Resources
Find proteins for Q92793 (Homo sapiens)
Explore Q92793 
Go to UniProtKB:  Q92793
PHAROS:  Q92793
GTEx:  ENSG00000005339 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ92793
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6XG
Query on 6XG

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B],
L [auth C]
3-[[1-(cyclopropylmethyl)-5-ethanoyl-6,7-dihydro-4~{H}-pyrazolo[4,3-c]pyridin-3-yl]amino]-~{N}-propan-2-yl-benzamide
C22 H29 N5 O2
KDQSAWDSOXZXES-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
I [auth B]
J [auth B]
E [auth A],
F [auth A],
G [auth A],
I [auth B],
J [auth B],
K [auth B],
M [auth C],
N [auth C]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6XG BindingDB:  5KTW IC50: 20 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.09 Å
  • R-Value Free: 0.176 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.163 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.614α = 90
b = 44.395β = 106.5
c = 66.811γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALAdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-11-02
    Type: Initial release
  • Version 1.1: 2016-12-21
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references