RCSB PDB - 5XST: novel orally efficacious inhibitors complexed with PARP1

 5XST

novel orally efficacious inhibitors complexed with PARP1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.203 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 8E6Click on this verticalbar to view details

This is version 1.2 of the entry. See complete history


Literature

Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors

Chen, X.Huan, X.Liu, Q.Wang, Y.He, Q.Tan, C.Chen, Y.Ding, J.Xu, Y.Miao, Z.Yang, C.

(2018) Eur J Med Chem 145: 389-403

  • DOI: https://doi.org/10.1016/j.ejmech.2018.01.018
  • Primary Citation of Related Structures:  
    5XSR, 5XST, 5XSU

  • PubMed Abstract: 

    The nuclear protein poly(ADP-ribose) polymerases-1/2 (PARP-1/2) are involved in DNA repair damaged by endogenous or exogenous process. And PARP-1/2 inhibitors have been proved to be clinically efficacious for DNA repair deficient tumors in the past decade. We have developed a series of 4,5,6,7-tetrahydrothienopyridin-2-yl benzimidazole carboxamides as novel and potent PARP-1/2 inhibitors. The best compound resulted from this series is compound 27 which displays excellent PARP-1 and PARP-2 inhibitory activity with IC 50 of 18 nM and 42 nM, respectively. Furthermore, it can selectively kill BRCA2 deficient V-C8 cells with a CC 50 of 920 nM. In the MDA-MB-436 (BRCA-1 mutant) xenograft model, this compound was well tolerated and showed single-agent activity. Based on the results above, compound 27 has been selected as a lead candidate targeting PARP-1/2 and its preclinical characterization is also underway.


  • Organizational Affiliation

    Synthetic Organic & Medicinal Chemistry Laboratory, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Poly [ADP-ribose] polymerase 1350Homo sapiensMutation(s): 1 
Gene Names: PARP1ADPRTPPOL
EC: 2.4.2.30 (PDB Primary Data), 2.4.2 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for P09874 (Homo sapiens)
Explore P09874 
Go to UniProtKB:  P09874
PHAROS:  P09874
GTEx:  ENSG00000143799 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP09874
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8E6
Query on 8E6

Download Ideal Coordinates CCD File 
B [auth A]6-fluoranyl-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-1~{H}-benzimidazole-4-carboxamide
C15 H13 F N4 O S
RVBDGUXYQPDTTD-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
8E6 BindingDB:  5XST IC50: 27 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.203 
  • Space Group: P 65 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.98α = 90
b = 93.98β = 90
c = 222.8γ = 120
Software Package:
Software NamePurpose
XSCALEdata scaling
PHASERmodel building
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 8E6Click on this verticalbar to view details

Entry History 

Deposition Data

  • Released Date: 2018-04-25 
  • Deposition Author(s): Liu, Q., Xu, Y.

Revision History  (Full details and data files)

  • Version 1.0: 2018-04-25
    Type: Initial release
  • Version 1.1: 2023-11-22
    Changes: Data collection, Database references, Refinement description
  • Version 1.2: 2024-10-16
    Changes: Structure summary