2R0U

Crystal Structure of Chek1 in Complex with Inhibitor 54

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history. 


Literature

Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase.

Garbaccio, R.M., Huang, S., Tasber, E.S., Fraley, M.E., Yan, Y., Munshi, S., Ikuta, M., Kuo, L., Kreatsoulas, C., Stirdivant, S., Drakas, B., Rickert, K., Walsh, E.S., Hamilton, K.A., Buser, C.A., Hardwick, J., Mao, X., Beck, S.C., Abrams, M.T., Tao, W., Lobell, R., Sepp-Lorenzino, L., Hartman, G.D.

(2007) Bioorg Med Chem Lett 17: 6280-6285

  • DOI: https://doi.org/10.1016/j.bmcl.2007.09.007
  • Primary Citation of Related Structures:  
    2R0U

  • PubMed Abstract: 

    From HTS lead 1, a novel benzoisoquinolinone class of ATP-competitive Chk1 inhibitors was devised and synthesized via a photochemical route. Using X-ray crystallography as a guide, potency was rapidly enhanced through the installation of a tethered basic amine designed to interact with an acidic residue (Glu91) in the enzyme pocket. Further SAR was explored at the solvent front and near to the H1 pocket and resulted in the discovery of low MW, sub-nanomolar inhibitors of Chk1.

    • Organizational Affiliation: 

    Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. robert_garbaccio@merck.com


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase Chk1323Homo sapiensMutation(s): 0 
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O14757 (Homo sapiens)
Explore O14757 
Go to UniProtKB:  O14757
PHAROS:  O14757
GTEx:  ENSG00000149554 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO14757
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
M54
Query on M54
Download Ideal Coordinates CCD File 
B [auth A]6-(3-aminopropyl)-4-(3-hydroxyphenyl)-9-(1H-pyrazol-4-yl)benzo[h]isoquinolin-1(2H)-one
C25 H22 N4 O2
BUSJQQYKXHYDNN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
M54 BindingDB:  2R0U IC50: 1 (nM) from 1 assay(s)
PDBBind:  2R0U IC50: 1 (nM) from 1 assay(s)
Binding MOAD:  2R0U IC50: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.26α = 90
b = 65.54β = 94.27
c = 58.5γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
CrystalCleardata collection
d*TREKdata reduction
d*TREKdata scaling
CNSphasing

Structure Validation

View Full Validation Report



View more in-depth experimental data
Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-10-30
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description