To identify, explore and validate new potential drug targets the Huber Laboratory uses a variety of different discovery approaches such as small molecule screens, biochemical assays, protein X-ray crystallography, chemical and protein-protein interaction proteomics, medicinal chemistry, RNAi, and genome-editing alongside classical molecular and cellular biology techniques aiming at the development of chemical probes that may provide leads for drug discovery.
Potent, selective and cell-permeable inhibitors that target key regulators of cellular signalling ("chemical probes") are valued reagents in both fundamental and applied biological research. They are essential tools for target validation and provide starting points for translational research projects.
DRUG TARGET DISCOVERY AND TARGET DECONVOLUTION
Chemical Proteomics & Thermal Stability Profiling
In order to understand the cellular targets of small molecules and drugs we use a combination of compound affinity chromatography coupled to protein mass spectrometry called "chemical proteomics" or "chemoproteomics". This technology allows us to identify the proteins which bind to compounds in cell or tissue lysates which, for example, can help to uncover the mechanism of action of compounds that have emerged from phenotypic screens or drugs that exhibit so-called "polypharmacology". The power of this approach is that in contrast to classical biochemical in vitro screening assays here the compound is exposed to an entire and competitive cellular proteome (thousands of natural full-length proteins with all posttranslational modifications) which provides a much more physiologically relevant context for evaluating the cellular effects of compound.
Recently, we have established a new methodology termed "Thermal Stability Profiling" which enables the profiling of small molecules and metabolites in intact living cells. Here we take advantage of the ligand-induced thermal stabilisation of proteins to unravel the molecular targets of drugs and other bioactive compounds.