Developing high-throughput MALDI TOF mass spectrometry for drug discovery

Ubiquitylation impacts almost every biological process in the cell. Alterations in ubiquitin metabolism are related to the pathogenesis of cancer, neurodegenerative diseases, metabolic syndromes and inflammatory disorders. The enzymes involved in the uniquitylation pathway (E1-E2-E3s ligases and Deubiquitylases) are the most promosing next-generation targets for the develoment of specific therapeutics. Due to a lack of technologies that enable the exploration of this system in detail, there is still a gap between basic scientists, translational researchers and clinicians. In order to fill this gap and bring more ubiquitin targeting drugs to the market we have developed a high-throughput MALDI-TOF mass spectrometry assay. Through the use of 1.536 well plate format targets and liquid handling robots, very large numbers of compunds can be screene in an enzymatic in vistro assay. We have successfully applied this screen recently to identify specific Deubiquitylase (DUB) inhibitors.
In this project we will further develop high-throughput MALDI mass spectrometry with Bruker Daltonics. We will apply this exciting new technology to perform the first MALDI TOF drug discovery assay for E2/E3 ligases which are also considered attractive drug targets.