Native Mass Spectrometry Guided Optimisation of 14-3-3 Molecular Glues for Cancer Therapeutics

使用药物将蛋白质“粘合”在一起，或“分子胶”，在一系列疾病领域是一种潜在的强大的治疗策略。然而，分子胶还没有被开发到接近其全部潜力的任何地方，这在很大程度上是因为缺乏告诉我们它们如何工作的工具，阻碍了它们的发展。该项目将采用、改进和使用一种名为自然质谱学的技术来指导分子胶的设计和优化。用于研究分子胶的天然质谱法是我们实验室最近开发的一种方法，它具有加快分子胶优化的令人兴奋的潜力。我们将专注于针对一种名为14-3-3的重要蛋白质相互作用的胶体的设计和优化，这种蛋白质在预防和抗击癌症方面发挥着特别重要的作用。因此，该项目将提供急需的新型癌症疗法，最终可用于解决难以治疗的癌症或围绕耐药性的问题。这是一个高度跨学科的项目，将在本土质谱学技术、化学生物学和药物设计方面提供世界级的培训。

Using drugs that 'stick' proteins together, or 'molecular glues', is a potentially hugely powerful therapeutic strategy across a range of disease areas. However, molecular glues have not been exploited to anywhere near their full potential in large part because their development has been hampered by a lack of tools that tell us how they work. This project will adapt, refine and use a technique called native mass spectrometry to guide the design and optimisation of molecular glues. The native mass spectrometry approach for studying molecular glues was recently developed in our laboratories and has exciting potential for speeding up the optimisation of molecular glues. We will focus on the design and optimisation of glues that target the interactions of an important protein called 14-3-3 which plays a particularly important role in preventing and fighting cancer. Thus the project will deliver much needed novel cancer therapies which can ultimately be used to tackle hard to treat cancers or problems surrounding drug resistance. This is a highly interdisciplinary project that will provide world-class training in native mass spectrometry techniques, chemical biology and drug design.