Selectivity profiling of 1,000 small molecule kinase inhibitors
Protein kinases are key regulator in signaling transduction and are involved in nearly all biological processes. But their function is often dysregulated in certain human diseases like cancer or inflammation. Hence, in pharmaceutical research, kinases have emerged as a leading class of drug targets. To date 39 small molecules are approved by the FDA and around 300 are in clinical trials. But only a subset of the ~500 human protein kinases have been subjected to drug discovery. Thus, a substantial part of the disease relevant kinome is still untargeted.
Using a library of 1,000 kinase inhibitors (clinical drugs and compounds from medicinal chemistry programs in the pharmaceutical industry) we aim to identify small molecules for the untargeted kinome. To profile the target space of all kinase inhibitors, we use the kinobead technology which features seven unselective small molecules immobilized on Sepharose beads for affinity kinome enrichment from cell lysate from cancer cells. This project highlights the ability of chemical proteomics to identify the target space and selectivity of small molecule kinase inhibitors. Finally we will generate a large data matrix showing that there already is chemical matter for the majority of the human kinome.