Combining multiple bullets against a sweet target - Fragment-based drug discovery to tackle cancer glycosylation

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Glycosylation is a ubiquitous posttranslational protein modification. Highly glycosylated mucin proteins are overexpressed as a hallmark of metastatic cancer, facilitating survival in circulation. Despite being a current clinical immunotherapy target, mucin biosynthesis is rarely the subject of drug discovery strategies. The addiction of mucins to glycosylation makes glycan biosynthesis an important drug target. This project, co-funded by GSK, will focus on the fragment-based drug discovery to generate an inhibitor against the most crucial nodal point of mucin glycosylation, the epimerase GALE. We will combine newly-available chemical space and modelling approaches to generate lead compounds with suitable interaction profiles. Evaluation in vitro and in vivo will feature enzymatic assays, microfluidics and cancer mouse models to develop a drug that hits mucin glycosylation, the sweet tooth of cancer.