Synthesis of novel FUT8 inhibitors as anticancer agents

人岩藻糖基转移酶VIII(FUT8)是一种在蛋白质翻译后修饰中起关键作用的酶，它在糖蛋白上的N-糖链上添加岩藻糖糖单元。这发挥了多种细胞功能，其中包括--至关重要的--对一系列蛋白质介导的相互作用的影响，包括细胞表面受体和信号蛋白之间的相互作用。在正常的生物过程中，这在控制细胞信号方面很重要，但由于FUT8酶的异常表达而导致的错误调节与多种疾病有关，特别是已知不仅是许多癌症的指标，而且是恶性肿瘤的驱动因素，特别是通过激活促进肿瘤细胞增殖的生长因子受体，放大导致转移的信号。已有文献表明，FUT8的上调与许多癌症有关，其过度表达的程度与疾病的严重程度和预后不良有关，这使得该酶成为药物干预潜在抗癌治疗的重要靶点。我们的目标是开发一系列具有战略针对性的化合物，作为FUT8酶的潜在抑制剂，从这些化合物中，我们将确定可以进一步开发成有效的、新型抗癌剂的先导化合物。我们将通过在这个为期一年的项目中完成三个目标来实现这一目标：使用系统的方法设计和合成一组FUT8底物类似物，从三个不同的构建块组装分子，并使用我们最近开发的一种新颖、灵敏、基于荧光的高通量酶分析来筛选这一化合物对FUT8的体外抑制作用。在这个项目完成后，我们将有一系列化合物专门抑制FUT8酶靶标，阻断细胞糖蛋白的岩藻糖化，包括细胞表面受体和信号蛋白，这些蛋白在癌症进展中发挥关键作用。被确认为抑制剂的化合物将在癌细胞培养中仔细鉴定其抗增殖特性，以期在更长期的后续项目中开发其作为抗癌治疗药物的潜力。

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.