Universiteit Leiden

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Development of kinase inhibitors and activity-based probes

Promotor: H.S. Overkleeft, J. Neefjes, Co-promotor: M. van der Stelt

Nora Liu
15 December 2016
Thesis in Leiden Repository

Kinases play a role in many diseases including cancer, diabetes and infection diseases. Therefore, kinases are interesting drug targets. Inhibitors for some kinases are already in use as clinical drugs, however due to resistance and side effects, but also to target kinases related to diseases for which there is currently no treatment, research on the discovery of new classes of kinase inhibitors is imperative. To achieve this, not only new inhibitor classes need to be designed and synthesized, but also tools to profile kinases in physiological context and to determine the selectivity of inhibitors are required. The research in this thesis has focused on the development of more potent AKT1 and FLT3 kinase inhibitors and on the synthesis and application of new chemical tools for the profiling of kinases involved in various types of cancers and other diseases.In this thesis, new powerful tools and assays have been developed that unite the fields of synthetic chemistry, protein biochemistry and cell biology for the global analysis of kinase expression and function. The value of chemical profiling as a method for functional proteome analysis has been further highlighted by its application as a screen to evaluate the potency and selectivity of kinase inhibitors.

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