Synthesis of novel FUT8 inhibitors as anticancer agents

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Human fucosyltransferase VIII (FUT8) is an enzyme that is involved in a key role in protein post-translational modification, adding a fucose sugar unit onto N-glycans present on glycoproteins. This plays a multitude of cellular functions, that includes-crucially-an influence over a range of protein-mediated interactions including those between cell surface receptors and signaling proteins. This is important in controlling cell signals in normal biological processes, but its misregulation resulting from abnormal expression of the FUT8 enzyme is implicated in a variety of diseases and in particular is known to be not only an indicator of many cancers, but also a driver of malignancy, especially through the activation of growth factor receptors that promote proliferation in tumour cells and amplifying signals that lead to metastasis. It has been well documented that FUT8 up-regulation is linked to many cancers and that the degree of its overexpression is correlated to disease severity and poor prognosis, making this enzyme an important target for potential anticancer therapies by pharmaceutical intervention. We aim to develop a series strategically targeted compounds as potential inhibitors of the FUT8 enzyme from which we will identify leads that can be further developed into potent, novel anticancer agents. We will achieve this by completing three objectives within this one-year project: design and synthesize a panel of FUT8 substrate analogue compounds using a systematic approach assembling molecules from three varied building blocks, and screen this collection of compounds for their in vitro inhibition of FUT8 using a novel, sensitive, fluorescence-based high-throughput enzyme assay that we have recently developed.At the completion of this project, we will have a series of compounds that will specifically inhibit the FUT8 enzyme target, blocking the fucosylation of cellular glycoproteins including cell surface receptors and signalling proteins that play key roles in cancer progression. Compounds identified as inhibitors will be carefully characterized for their antiproliferative properties in cancer cell cultures, towards their potential development as anticancer therapeutics in longer-term follow-up projects.