SYSTEMATIC SELECTIVITY PROFILING OF KINASE INHIBITOR DRUGS BY CHEMICAL PROTEOMICS

Project Members:	Fiona Pachl
Cooperation:	-
Contact:	Fiona Pachl

Cancer is a leading cause of death wordwide, it accounted for 7.9 million (about 13%) deaths in 2007. Deaths from cancer are projected to increase to 12 million in 2030. For this reason, the development of new cancer therapies plays a crucial role. Small molecule kinase inhibitors have an important role as drugs in targeted therapy. To date, eight kinase inhibitors have beed approved for clinical application. Many of these inhibitors are not completely specific for their primary target but still bind a number of other kinases. Selectivity profiling is essential to estimate the therapeutic potential of a kinsae inhibitor. The aim of this thesis was to profile the selectivity of lapatinib, erlotinib and gefitinib. Due to the identification of new targets one may explain possible side effects and suggest possibly new applications for already approved drugs. To determine the selectivity, kinobead competition assays and subsequent quantitative analysed by mass spectrometry were performed. The binding profiles of the kinase inhibitors to as many human proteins as possible were performed in an unbiased way and under physiological conditions. One focus of the work was also to establish different applied technologies at the Institute. In this context, a script for data processing of quantitative MS data was developed and the MS method optimized. With this a robust analysis of the experimental data was possible. The results show a narrow selectivity profile for the EGFR inhibitors lapatinib, erlotinib and gefitinib. The potent binding of erlotinib and gefitinib to GAK was confirmed. Also sorafenib has a relatively narrow selectivity range. Results show that kinobead competition assay combined to quantitative mass spectrometry is promissing but challenging and a valuable tool for drug discovery.