Chemical genetic approaches for target validation
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.
- Wel, T. van der
- 22 January 2020
- Thesis in Leiden Repository
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 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.