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Article Dans Une Revue ChemBioChem Année : 2005

Structure-aided optimization of kinase inhibitors derived from alsterpaullone

C. Kunick
  • Fonction : Auteur
Z. Zeng
  • Fonction : Auteur
R. Gussio
  • Fonction : Auteur
D. Zaharevitz
  • Fonction : Auteur
M. Leost
  • Fonction : Auteur
F. Totzke
  • Fonction : Auteur
C. Schachtele
  • Fonction : Auteur
Kubbutat M. H.
  • Fonction : Auteur
T. Lemcke
  • Fonction : Auteur

Résumé

In order to perform computer-aided design of novel alsterpaullone derivatives, the vicinity of the entrance to the ATP-binding site was scanned for areas that could be useful as anchoring points for additional protein-ligand interactions. Based on the alignment of alsterpaullone in a CDK1/cyclin B homology model, substituents were attached to the 2-position of the parent scaffold to enable contacts within the identified areas. Synthesis of the designed structures revealed three derivatives (3-5) with kinase-inhibitory activity similar to alsterpaullone. The novel 2-cyanoethylalsterpaullone (7) proved to be the most potent paullone described so far, exhibiting inhibitory concentrations for CDK1/ cyclin B and GSK-3beta in the picomolar range.
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Dates et versions

hal-00018743 , version 1 (08-02-2006)

Identifiants

  • HAL Id : hal-00018743 , version 1

Citer

C. Kunick, Z. Zeng, R. Gussio, D. Zaharevitz, M. Leost, et al.. Structure-aided optimization of kinase inhibitors derived from alsterpaullone. ChemBioChem, 2005, 6, pp.1-9. ⟨hal-00018743⟩
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