Structure-Aided Optimization of Kinase Inhibitors
 Derived from Alsterpaullone


 

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ChemBioChem, 2005, 6, 3, 541-549.

Conrad Kunick, Prof. 1 *, Zhihong Zeng, Dr. 2, Rick Gussio, Dr. 3, Daniel Zaharevitz, Dr. 3, Maryse Leost 4, Frank Totzke, Dr. 5, Christoph Schächtele, Dr. 5, Michael H. G. Kubbutat, Dr. 5, Laurent Meijer, Prof. 4, Thomas Lemcke, Dr. 2

1Institut für Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany, Fax: (+49) 531-391-2799
2Institut für Pharmazie, Universität Hamburg, Bundesstraße 45, 20146 Hamburg, Germany
3Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland 20852, USA
4Centre National de la Recherche Scientifique, Station Biologique, B. P. 74, 29682 Roscoff, France
5ProQinase GmbH, Breisacher Straße 117, 79106 Freiburg, Germany

email:
Prof. Conrad Kunick

*Correspondence to Conrad Kunick, Institut für Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany, Fax: (+49) 531-391-2799

Keywords:enzymes • inhibitors • lactams • molecular modeling • paullones • proteins

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-3 in the picomolar range.

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