Developing drug discovery assays for primary human immune cells using high-throughput MALDI-TOF mass spectrometry

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In the high-throughput screening (HTS) process of the drug discovery pipeline, in vitro assays are used to evaluate the efficacy of compound libraries against a specific drug target. Currently, fluorescence and chemiluminescence are the most common methods used in HTS assays. As an exciting new tool, next generation matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS) instruments have been implemented for HTS approaches in drug discovery. They provide the advantage of being highly sensitive, robust, fast and label-free in comparison to the currently used fluorescence-based methods. Moreover, these new MALDI-TOF-MS instruments can now be integrated with full automation platforms and workflows. In recent years, it has been demonstrated that MALDI-TOF MS based in vitro assays can be used to directly monitor products and substrates of a diverse range of enzymatic reactions. These direct readouts have since been used for screening small molecule activators and inhibitors against a variety of protein targets and shown to correlate with fluorescent based assay results. Transferring this technique onto large scale drug discovery workflows will provide the great advantage to work with label free substrates. MALDI-TOF MS can also be used for cellular assays, although this technique is not well established in the industrial setting and therefore requires characterisation of cells. There is a great need for biologically relevant models in order to improve the translation from possible drug compound identifications into the clinic. In particular, this applies to human primary and induced pluripotent stem cell derived immune cells, which are already used in early phase drug discovery, to better describe the human biology. They play important roles in auto-immunity and in cancer. Currently, cellular assays are based on established cell lines and therefore using human primary and induced pluripotent stem cell derived immune cells assays will allow the implementation of biologically relevant models in the drug discovery pipeline which can improve the efficiency of HTS processes.The PhD project will focus on the development of biochemical high-throughput screening workflows for drug discovery, as well as explore and further understand cell-based models on a MALDI-TOF MS platform. These techniques will be applied to attractive targets within the immune response, as well as primary immune cells as they are targets for anti-inflammatory drugs and drugs in immune oncology. Recently, many drug discovery campaigns are focusing on immunotherapy that uses the own immune system to fight cancer. This project is based in the laboratory of Professor Matthias Trost at Newcastle University and will be conducted in collaboration with GlaxoSmithKline (GSK).