Identification and Optimisation of Inhibitors of the Aurora A/N-Myc Protein-Protein Interaction in Neuroblastoma

该项目将专注于鉴定可以破坏Aurora A/N-Myc蛋白质相互作用的化合物。N-Myc蛋白通常在儿科肿瘤神经母细胞瘤中过表达，并且与较差的预后相关。N-Myc是高度可变的，被认为是“不可药用的”。然而，Aurora A/N-Myc复合物含有可被小分子靶向并破坏相互作用的位点。当N-Myc从该复合物中去除时，磷酸化位点变得可接近，其靶向蛋白质进行蛋白酶体降解。N-Myc的减少导致细胞死亡，并显示出作为某些癌症治疗的前景。该项目将包括虚拟筛选，以确定片段和化合物库的初始命中，生物测定，以评估结合强度和合成类似物，以优化命中。

The project will focus on identifying compounds which can disrupt the Aurora A/N-Myc protein-protein interaction. The N-Myc protein is often overexpressed in the paediatric tumour Neuroblastoma and correlates with a poorer prognosis. N-Myc is highly variable and is considered "undruggable". However the Aurora A/N-Myc complex contains sites which could be targeted by small molecules and disrupt the interaction. When N-Myc is removed from this complex, sites of phosphorylation become accessible, which targets the protein for proteasomal degradation. Reduction of N-Myc leads to cell death and shows promise as a therapy for some cancers.The project will involve virtual screening to identify initial hits from fragment and compound libraries, biological assays to assess binding strength and synthesis of analogues to optimise hits.