Pharmacological Inhibitors of CDKs and GSK3

Using these simple methods, a large number of pharmacological inhibitors have been discovered and characterised. Surprisingly many CDK inhibitors, but not all, are also excellent inhibitors of GSK-3 (Leclerc et al. 2001). The properties of these pharmacological inhibitors have been extensively reviewed both for CDKs (Hardcastle et al. 2002; Knockaert et al. 2002a; Sausville 2002; Fischer et al. 2003; Monaco and Vallano 2003) and for GSK-3 (Leclerc et al. 2001; Dorronsoro et al. 2002; Martinez et al. 2002; L. Meijer et al., in preparation). We will thus not duplicate these reviews, but instead summarise the properties shared by these inhibitors in a few lines and provide a more detailed review on the paullones, a family of CDK and GSK-3 dual inhibitors. Essentially all inhibitors share the following properties:

• They are small molecular weight compounds (<600 Da).

• They are flat, rather hydrophobic, heterocycles.

• They act by competing with ATP for binding to the catalytic site of the ki-nase.

• They bind in the ATP-binding pocket, located between the small and large lobe of the kinase.

• The interactions with the kinase are predominantly hydrophobic and Van der Waals type.

• The inhibitors also bind through two or three hydrogen bonds with backbone atoms of leucine-83 and glutamic acid 81 (in CDK2) and the corresponding valine-135 and aspartic acid 133 in GSK-3 (Meijer et al. 2003).

Was this article helpful?

0 0

Post a comment