5XXH

Crystal Structure Analysis of the CBP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.62 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.192 

Starting Model: experimental
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This is version 2.1 of the entry. See complete history


Literature

Discovery and optimization of 1-(1H-indol-1-yl)ethanone derivatives as CBP/EP300 bromodomain inhibitors for the treatment of castration-resistant prostate cancer.

Xiang, Q.Wang, C.Zhang, Y.Xue, X.Song, M.Zhang, C.Li, C.Wu, C.Li, K.Hui, X.Zhou, Y.Smaill, J.B.Patterson, A.V.Wu, D.Ding, K.Xu, Y.

(2018) Eur J Med Chem 147: 238-252

  • DOI: https://doi.org/10.1016/j.ejmech.2018.01.087
  • Primary Citation of Related Structures:  
    5XXH

  • PubMed Abstract: 

    The CREB (cAMP responsive element binding protein) binding protein (CBP) and its homolog EP300 have emerged as new therapeutic targets for the treatment of cancer and inflammatory diseases. Here we report the identification, optimization and evaluation of 1-(1H-indol-1-yl)ethanone derivatives as CBP/EP300 inhibitors starting from fragment-based virtual screening (FBVS). A cocrystal structure of the inhibitor (22e) in complex with CBP provides a solid structural basis for further optimization. The most potent compound 32h binds to the CBP bromodomain and has an IC 50 value of 0.037 μM in the AlphaScreen assay which was 2 times more potent than the reported CBP bromodomain inhibitor SGC-CBP30 in our hands. 32h also exhibit high selectivity for CBP/EP300 over other bromodomain-containing proteins. Notably, the ester derivative (29h) of compound 32h markedly inhibits cell growth in several prostate cancer cell lines including LNCaP, 22Rv1 and LNCaP derived C4-2B. Compound 29h suppresses the mRNA expression of full length AR (AR-FL), AR target genes and other oncogene in LNCaP cells. 29h also reduces the expression of PSA, the biomarker of prostate cancer. CBP/EP300 inhibitor 29h represents a promising lead compound for the development of new therapeutics for the treatment of castration-resistant prostate cancer.


  • Organizational Affiliation

    Guangdong Provincial Key Laboratory of Biocomputing, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CREB-binding protein133Homo sapiensMutation(s): 0 
Gene Names: CREBBPCBP
EC: 2.3.1.48 (PDB Primary Data), 2.3.1 (UniProt)
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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.62 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.192 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.32α = 90
b = 44.32β = 90
c = 121.292γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
Aimlessdata scaling
PDB_EXTRACTdata extraction
iMOSFLMdata reduction
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Natural Science Foundation of China (NSFC)China--

Revision History  (Full details and data files)

  • Version 1.0: 2018-06-13
    Type: Initial release
  • Version 2.0: 2023-10-18
    Type: Coordinate replacement
    Reason: Occupancy of atoms on special symmetry positions
    Changes: Atomic model, Author supporting evidence, Data collection, Database references, Derived calculations, Other, Refinement description, Source and taxonomy, Structure summary
  • Version 2.1: 2023-11-22
    Changes: Refinement description