Understanding and Manipulating the Protein-Protein Interactions of Aurora A Kinase using Chemical Biology approaches

化学探针的独特之处在于它们可以以剂量和时间依赖性的方式调节蛋白质功能。它们可用于了解蛋白质与疾病过程的相关性，并作为药物发现的起点。虽然鉴定蛋白质-蛋白质相互作用（PPI）抑制剂的方法正在建立，但靶向涉及内在无序区（IDR）的PPI的方法尚未得到很好的开发。该项目将开发使物理科学方法-特别是利用共价蛋白标记-来表征，抑制和跟踪内在无序蛋白质的细胞内相互作用，重点是Aurora A激酶与N-MYC，TPX-2和TACC 3的相互作用。Aurora A在细胞生命周期中起着至关重要的作用，例如在细胞分裂中，这一过程在癌症中变得有缺陷，使其成为抗癌药物发现工作的焦点。其目的和目标与LifeArc的CASE学生将建立在广泛的初步结构数据上，以（i）了解Aurora A PPI的预组织肽模拟调节剂的影响，（ii）利用动态连接筛选来鉴定Aurora A PPI的肽-小分子杂合调节剂和（iii）设计具有用于细胞内Aurora A标记的新反应性弹头的共价化学探针。学生将获得综合技能，肽/蛋白质化学和生物物理学，并通过与项目合作伙伴（i）获得配体发现方法的技术能力（ii）潜在的应用和益处这些工具的开发将解决缺乏物理科学方法来识别IDR的化学探针的问题，并揭示对Aurora A激酶关键调控因子的功能作用的见解以揭示替代治疗策略。调节PPI对于未来医疗保健创新和治疗具有巨大社会负担的多种疾病（例如癌症、炎症性疾病等）至关重要。因此，开展这项研究将有助于EPSRC的繁荣成果：健康国家和21世纪世纪产品。

Chemical probes are unique in that they can in a dose and time dependent manner modulate protein function. They can be used to understand the relevance of a protein to a disease process and as starting points for drug discovery. Whilst methods to identify inhibitors of protein-protein interactions (PPI) are becoming established, methods to target PPIs involving intrinsically disordered regions (IDRs) are not well developed. This project will develop enabling physical sciences methods - specifically exploiting covalent protein labelling - to characterize, inhibit and track the intracellular interactions of intrinsically disordered proteins focusing on interactions of the Aurora A Kinase with N-MYC, TPX-2 and TACC3. Aurora A plays an essential role in the cells life-cycle e.g. in cell-division, a process that becomes defective in cancer making it a focus of anticancer drug discovery efforts.Its aims and objectives The CASE studentship with LifeArc will build on extensive preliminary structural data to (i) understand the affects of pre-organise peptidomimetic modulators of Aurora A PPIs, (ii) exploit dynamic ligation screening to identify peptide-small molecule hybrid modulators of Aurora A PPIs and (iii) design covalent chemical probes with new reactive warheads for in cell Aurora A Labelling. The student will gain skills in synthesis, peptide/protein chemistry and biophysics and through collaboration with the project partner (i) gain technical competences in ligand discovery methods (ii) develop a translation mindset.Potential applications and benefitsDevelopment of these tools will address a lack of physical sciences approaches to identify chemical probes for IDRs and reveal insight on the functional role of key regulators of the Aurora A kinase to reveal alternative therapeutic strategies. Modulating PPIs is critical to future healthcare innovation and treatment of multiple diseases with huge societal burdens, e.g. cancer, inflammatory diseases etc. Pursuing this research will thus contribute to the EPSRC prosperity outcomes: Healthy Nation and 21st Century products.