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Structure-aided optimization of kinase inhibitors derived from alsterpaullone

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Kunick, C. | Zeng, Z. | Gussio, R. | Zaharevitz, D. | Leost, M. | Totzke, F. | Schachtele, C. | M. H., Kubbutat | Meijer, L. | Lemcke, T.

Edité par CCSD ; Wiley-VCH Verlag -

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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