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

使用将蛋白质“粘”在一起的药物或“分子胶”，是一种潜在的强大的治疗策略，适用于一系列疾病领域。然而，分子胶在很大程度上还没有被开发到接近其全部潜力的任何地方，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、改进和使用一种称为天然质谱法的技术来指导分子胶的设计和优化。用于研究分子胶的原生质谱方法是最近在我们的实验室开发的，在加速分子胶的优化方面具有令人兴奋的潜力。我们将专注于设计和优化针对一种叫做14-3-3的重要蛋白质的相互作用的胶水，这种蛋白质在预防和对抗癌症方面起着特别重要的作用。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，将提供世界级的本土质谱技术、化学生物学和药物设计方面的培训。

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.