This medicinal chemistry group forms part of the Research Group PhosphoSites

Protein kinases have emerged as an important class of pharmaceutical targets because of the key role they play in signal transduction and the fact that they are often dysregulated in diseases such as cancer, type 2 diabetes, neurodegenerative disorders and cardiovascular dis­ease. Most of the drugs currently under development target the ATP binding site, but this means that there is a lack of specificity for a given kinase. In this project, which was started in 2005, we are aiming to develop more selective drugs with lower inherent risks of side effects. We are currently targeting a regulatory site (a so-called ‘PIF pocket’) that is present in protein kinases of the AGC family including several pharmaceutically interesting targets such as PKB (AKT), PDK1, PRK, SGK, MSK, ROCK kinase and PKCs. The PIF pocket was discovered and characterized by our collaborator, Dr R. M. Biondi. By exploiting the greater variability of the hydrophobic pocket we intend to develop more selective non-ATP competitive com­pounds which could either inhibit or activate the AGC kinase of interest. We have succeeded in identifying several active compounds that can mimic phosphorylation-dependent confor­mational transitions in protein kinases by binding to the PIF pocket. To our knowledge, this is the first time that this has been achieved using small-molecule compounds. At present, the scaffolds are being optimized to generate an appropriate lead structure that will be further derivatized by parallel synthesis.