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PDBsum entry 2hxl
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protein ligands links
Transferase PDB id
2hxl

 

 

 

 

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JSmol PyMol  
Contents
Protein chain
272 a.a. *
Ligands
422
Waters ×115
* Residue conservation analysis
PDB id:
2hxl
Name: Transferase
Title: Crystal structure of chek1 in complex with inhibitor 1
Structure: Serine/threonine-protein kinase chk1. Chain: a. Fragment: chek1 kinase domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: chek1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
1.80Å     R-factor:   0.240     R-free:   0.270
Authors: Y.Yan
Key ref: S.Huang et al. (2006). Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors. Bioorg Med Chem Lett, 16, 5907-5912. PubMed id: 16990002 DOI: 10.1016/j.bmcl.2006.08.053
Date:
03-Aug-06     Release date:   19-Jun-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
O14757  (CHK1_HUMAN) -  Serine/threonine-protein kinase Chk1 from Homo sapiens
Seq:
Struc: 		476 a.a.
272 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.1  - non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
L-seryl-[protein]
 + ATP
 = O-phospho-L-seryl-[protein]
 + ADP
 + H(+)
L-threonyl-[protein]
 + ATP
 = O-phospho-L-threonyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1016/j.bmcl.2006.08.053 Bioorg Med Chem Lett 16:5907-5912 (2006)
PubMed id: 16990002  
 
 
Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors.
S.Huang, R.M.Garbaccio, M.E.Fraley, J.Steen, C.Kreatsoulas, G.Hartman, S.Stirdivant, B.Drakas, K.Rickert, E.Walsh, K.Hamilton, C.A.Buser, J.Hardwick, X.Mao, M.Abrams, S.Beck, W.Tao, R.Lobell, L.Sepp-Lorenzino, Y.Yan, M.Ikuta, J.Z.Murphy, V.Sardana, S.Munshi, L.Kuo, M.Reilly, E.Mahan.
 
  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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19362847 P.Jake Slavish, Q.Jiang, X.Cui, S.W.Morris, and T.R.Webb (2009).
Design and synthesis of a novel tyrosine kinase inhibitor template.
  Bioorg Med Chem, 17, 3308-3316.  
17854022 K.L.Arrington, and V.Y.Dudkin (2007).
Novel Inhibitors of Checkpoint Kinase 1.
  ChemMedChem, 2, 1571-1585.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.

 

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