A “hot” approach for understanding drug action and identifying new drug targets
How do successful drugs actually work? And how can we identify new targets for drug discovery to enable the development of novel potential therapeutics? A key challenge for scientists in academia and the pharmaceutical industry is to find out how small molecules such as drugs or cellular metabolites act within a cell – who are the mediators and effectors required for a drug or metabolite to exert their effect e.g. on cell proliferation, shape etc.? Based on the simple fact that interaction between a small molecule - such as a drug - and a given target protein increases the thermal stability of that protein, scientists at CeMM have developed a new state-of-art approach to reveal the cellular proteins that are engaged by small molecules and metabolites. By refining the established cellular thermal shift assay (CETSA) approach in which cells are treated with a small molecule and then heated to measure the differential protein stability upon target engagement and combining it with modern protein mass spectrometry a broad view of small molecule-protein interactions is provided. A particular advantage of the new methodology is the fact that the assay works with intact living cells and thus reflects a more natural (“physiological”) context in which the small molecule and its target proteins interact without any interference considering compound uptake, efflux, metabolism as well as cellular compartments. A potential future application includes the use of patient material to identify patient specific bio markers to enable personalized medicine.
Kilian V M Huber, Karin M Olek, André C Müller, Chris Soon Heng Tan, Keiryn L Bennett, Jacques Colinge, Giulio Superti-Furga. Proteome-wide drug and metabolite interaction mapping by thermal-stability profiling. Nature Methods, doi:10.1038/nmeth.3590.
CeMM gratefully acknowledges funding from the Austrian Academy of Sciences, the European Union (FP7 259348, ASSET) and from the Austrian Science Fund (FWF F4711, MPN).