Drug development is a time- and resource-consuming process that starts with the discovery and validation of a (protein) target that contributes to pathogenesis or disease progression. One of the... Show moreDrug development is a time- and resource-consuming process that starts with the discovery and validation of a (protein) target that contributes to pathogenesis or disease progression. One of the essential steps in this process is to validate that pharmacological modulation (e.g. inhibition) of the target leads to the desired phenotype, a process which is collectively referred to as target validation. Target validation heavily relies on the availability of suitable chemical tools to study engagement of the compound to the intended biological target. The development of selective chemical tools can be challenging to achieve due to the off-target activity towards structurally and/or functionally related homologs, e.g. other members within the same protein class. The field of chemical genetics combines the specificity of genetics with benefits of acute, pharmacological modulation by small molecules. This thesis describes chemical genetic approaches that can be used for target engagement and target validation studies of two different enzyme classes: kinases and serine hydrolases. Show less
The disease acute myeloid leukemia (AML) is characterized by fast progression and low survival rates. Fms-like tyrosine kinase 3 (FLT3) receptor mutations have been identified as a driver mutation... Show moreThe disease acute myeloid leukemia (AML) is characterized by fast progression and low survival rates. Fms-like tyrosine kinase 3 (FLT3) receptor mutations have been identified as a driver mutation in cancer progression in a subgroup of AML patients. Clinical trials have shown emergence of drug resistant mutants, emphasizing the ongoing need for new chemical matter to enable the treatment of this disease. This thesis describes the discovery and evaluation of new chemical series of FLT3 inhibitors and furthermore employs label-free chemical proteomics techniques to evaluate new and existing FLT3 inhibitors for their cellular kinase off-target profile. Show less
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... Show moreKinases 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. Show less
Linden, O.P.J. van; Farenc, C.; Zoutman, W.H.; Hameetman, L.; Wijtmans, M.; Leurs, R.; ... ; Esch, I.J.P. de 2012