Synthesis of novel FUT8 inhibitors as anticancer agents

新型 FUT8 抑制剂作为抗癌药物的合成

• 批准号: 576974-2022
• 负责人: Giguere, DenisD
• 金额: $ 1.82万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748608
• 关键词: Synthesis; novel; FUT8; inhibitors; anticancer

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.

人岩藻糖基转移酶VIII（FUT 8）是一种在蛋白质翻译后修饰中发挥关键作用的酶，将岩藻糖单元添加到糖蛋白上存在的N-聚糖上。这发挥了多种细胞功能，其中包括-至关重要的-一系列蛋白质介导的相互作用，包括细胞表面受体和信号蛋白之间的影响。这在控制正常生物过程中的细胞信号中是重要的，但是由FUT 8酶的异常表达引起的其失调与多种疾病有关，并且特别地已知其不仅是许多癌症的指标，而且还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并放大导致转移的信号。已经有充分的证据表明，FUT 8上调与许多癌症有关，并且其过表达的程度与疾病严重程度和不良预后相关，使得这种酶成为通过药物干预进行潜在抗癌治疗的重要靶点。我们的目标是开发一系列战略靶向化合物作为FUT 8酶的潜在抑制剂，从中我们将确定可以进一步开发成有效的新型抗癌药物的线索。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：设计和合成一组FUT 8底物类似物化合物，使用系统的方法从三个不同的结构单元组装分子，并使用我们最近开发的一种新的、灵敏的、基于荧光的高通量酶测定法筛选这些化合物的体外抑制FUT 8。在该项目完成时，我们将有一系列的化合物，可以特异性地抑制FUT 8酶靶点，阻断细胞糖蛋白的岩藻糖基化，包括细胞表面受体和在癌症进展中起关键作用的信号蛋白。被鉴定为抑制剂的化合物将被仔细表征其在癌细胞培养物中的抗增殖特性，以在长期随访项目中作为抗癌治疗剂进行潜在开发。