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蛋白质翻译后修饰。高度糖基化的粘蛋白过度表达是转移性癌症的标志，有助于在循环中存活。尽管粘蛋白生物合成目前是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使糖的生物合成成为重要的药物靶点。该项目由葛兰素史克共同资助，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的结点--表异构酶Gale的抑制剂。我们将结合新的可用的化学空间和建模方法来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以酶分析、微流体和癌症小鼠模型为特色，以开发一种打击粘蛋白糖基化的药物，粘蛋白糖基化是癌症的甜味剂。

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.