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

结合多种子弹对抗甜蜜的目标——基于片段的药物发现来解决癌症糖基化问题

• 批准号: 2272112
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2272112
• 关键词: Combining; multiple; bullets; against; sweet

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.

糖基化是一种普遍存在的翻译后蛋白质修饰。高度糖基化的粘蛋白蛋白过表达作为转移性癌的标志，从而促进了循环中的生存率。尽管目前是临床免疫疗法靶标，但粘蛋白生物合成很少是药物发现策略的主题。粘蛋白对糖基化的成瘾使聚糖生物合成成为重要的药物靶点。该项目由GSK共同资助，将集中在基于碎片的药物发现上，以生成抑制剂，以针对粘蛋白糖基化最关键的淋巴结点，即表达酶大风。我们将结合新的化学空间和建模方法，以生成具有合适相互作用曲线的铅化合物。体外和体内的评估将采用酶促测定，微流体和癌症小鼠模型，以开发一种粘蛋白糖基化的药物，即癌症的甜食。