转移占癌症相关死亡率的大部分,代表着巨大的健康和经济负担。导致转移的机制之一是高唾液酸化,以肿瘤表面唾液酸化聚糖过多为特征,这导致细胞与原始肿瘤的排斥和脱离。一旦肿瘤细胞动员起来,唾液酸化聚糖通过自身分子模拟劫持自然杀伤T细胞,并激活分子事件的下游级联,从而抑制针对癌细胞的细胞毒性和炎症反应,最终导致免疫逃避。唾液酸化由称为唾液酸转移酶(STs)的酶家族介导。催化唾液酸残基从供体转移,CMP-唾液酸,在细胞表面上的受体如N-乙酰半乳糖胺的末端。STs的上调会使肿瘤的唾液酸过度增加多达60%,这被认为是几种类型癌症(如胰腺癌)的独特标志。乳房,和卵巢癌。因此,抑制STs已成为预防转移的潜在策略.在这次全面审查中,我们讨论了使用基于配体的药物设计和天然和合成实体的高通量筛选设计新型唾液酸转移酶抑制剂的最新进展,强调最成功的方法。我们分析了选择性设计的局限性和挑战,强力,和细胞渗透性ST抑制剂阻碍了ST抑制剂进一步进入临床试验的发展。最后,我们分析了新出现的机会,包括先进的给药方法,这进一步增加了这些抑制剂的潜力,以丰富的新型治疗方法来对抗转移。
Metastasis accounts for the majority of cancer-associated mortalities, representing a huge health and economic burden. One of the mechanisms that enables metastasis is hypersialylation, characterized by an overabundance of sialylated glycans on the tumor surface, which leads to repulsion and detachment of cells from the original tumor. Once the tumor cells are mobilized, sialylated glycans hijack the natural killer T-cells through self-molecular mimicry and activatea downstream cascade of molecular events that result in inhibition of cytotoxicity and inflammatory responses against cancer cells, ultimately leading to immune evasion. Sialylation is mediated by a family of enzymes known as sialyltransferases (STs), which catalyse the transfer of sialic acid residue from the donor, CMP-sialic acid, onto the terminal end of an acceptor such as N-acetylgalactosamine on the cell-surface. Upregulation of STs increases tumor hypersialylation by up to 60% which is considered a distinctive hallmark of several types of cancers such as pancreatic, breast, and ovarian cancer. Therefore, inhibiting STs has emerged as a potential strategy to prevent metastasis. In this comprehensive
review, we discuss the recent advances in designing novel
sialyltransferase inhibitors using ligand-based drug design and high-throughput screening of natural and synthetic entities, emphasizing the most successful approaches. We analyse the limitations and challenges of designing selective, potent, and cell-permeable ST inhibitors that hindered further development of ST inhibitors into clinical trials. We conclude by analysing emerging opportunities, including advanced delivery methods which further increase the potential of these inhibitors to enrich the clinics with novel therapeutics to combat metastasis.