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

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作为转移性癌症的标志过度表达，促进了循环中的生存。尽管黏液蛋白生物合成是目前临床免疫治疗的靶点，但很少成为药物发现策略的主题。粘蛋白对糖基化的依赖性使得糖基生物合成成为一个重要的药物靶点。该项目由GSK共同资助，将专注于基于片段的药物发现，以产生一种针对粘蛋白糖基化最关键节点（epimerase GALE）的抑制剂。我们将结合新的可用化学空间和建模方法来生成具有合适相互作用谱的先导化合物。体外和体内的评估将包括酶分析、微流体和癌症小鼠模型，以开发一种能够打击黏液糖基化的药物，这是癌症的甜食。

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.