2HY0

crystal structure of chek1 in complex with inhibitor 22


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.230 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors.

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

(2006) Bioorg Med Chem Lett 16: 5907-5912

  • DOI: https://doi.org/10.1016/j.bmcl.2006.08.053
  • Primary Citation of Related Structures:  
    2HXL, 2HXQ, 2HY0

  • PubMed Abstract: 

    Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds.


  • Organizational Affiliation

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


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase Chk1322Homo sapiensMutation(s): 0 
Gene Names: CHEK1
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
306
Query on 306

Download Ideal Coordinates CCD File 
B [auth A]3-[5-(PIPERIDIN-1-YLMETHYL)-1H-INDOL-2-YL]-6-(1H-PYRAZOL-4-YL)QUINOLIN-2(1H)-ONE
C26 H25 N5 O
JRWKQEATLFJZFB-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
306 Binding MOAD:  2HY0 IC50: 0.65 (nM) from 1 assay(s)
PDBBind:  2HY0 IC50: 0.65 (nM) from 1 assay(s)
BindingDB:  2HY0 IC50: 0.65 (nM) from 1 assay(s)
EC50: 97 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.230 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.91α = 90
b = 65.65β = 94.09
c = 57.86γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
CNSrefinement
d*TREKdata reduction
d*TREKdata scaling
CNSphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2007-06-19 
  • Deposition Author(s): Yan, Y.

Revision History  (Full details and data files)

  • Version 1.0: 2007-06-19
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description