Stabilizers of the interaction between 14-3-3 and hDM2 and hDMX

瞬态蛋白-蛋白相互作用（PPIs）控制着与健康和疾病相关的所有细胞过程。因此，对个体ppi的选择性调节将有助于更好地理解生物学机制，并为治疗干预提供新的机会。p53是一种重要的肿瘤抑制因子，参与DNA修复、细胞增殖抑制和细胞周期调节。P53通过与hDM2和/或hDMX相互作用负调控。这些蛋白调节p53的定位，物理阻断其与DNA的相互作用，并通过泛素化和随后的蛋白水解降解协同作用影响p53的降解。反过来，hDM2和hDMX的功能是通过磷酸化依赖与适配器蛋白14-3-3的相互作用来调节的。鉴于hDM2和hDMX在许多癌症中过表达，p53/hDM2(X)相互作用作为药物发现靶点受到了相当大的关注。本博士项目将通过鉴定和优化hDM2/14-3-3和hDMX/14-3-3的稳定剂，寻求另一种靶向致癌p53通路的方法。该项目将利用我们的药物发现能力工具箱、关于hDM2/14-3-3和hDMX/14-3-3相互作用性质的内部晶体学和生物物理数据，以及从常规筛选和动态片段连接实验中确定的击中物质。将采用一系列适合目标的方法，包括：计算预测，肽化学，小分子合成，筛选技术，生物物理学和结构分子生物学。作为与阿斯利康合作的CASE学生，在哥德堡的研究实习将成为学生的一部分。这将允许设计、合成和测试候选PPI稳定剂，以发现选择性和细胞渗透性调节剂。

Transient protein-protein interactions (PPIs) control all cellular processes relevant to health and disease. Selective modulation of individual PPIs would thus facilitate both a greater understanding of biological mechanisms and provide new opportunities for therapeutic intervention. p53 is a critical tumour suppressor involved in DNA repair, inhibition of cell proliferation and cell cycle regulation. P53 is negatively regulated through interaction with hDM2 and/or hDMX. These proteins regulate localization of p53, physically block its interaction with DNA and act in concert to effect p53 degradation through ubiquitination and subsequent proteolytic degradation. In turn hDM2 and hDMX function is regulated through phosphorylation dependent interaction with the adaptor protein 14-3-3. Given that hDM2 and hDMX are overexpressed in numerous cancers, the p53/hDM2(X) interaction has received considerable attention as a drug-discovery target. This PhD project will pursue an alternative approach to target the oncogenic p53 pathway by identification and optimization of stabilizers of hDM2/14-3-3 and hDMX/14-3-3. The project will exploit our toolkit of enabling drug discovery capabilities, in house crystallographic and biophysical data on the nature of the hDM2/14-3-3 and hDMX/14-3-3 interactions together with hit matter identified from conventional screening and dynamic fragment ligation experiments. A range of methods appropriate to the target will be employed including: computational prediction, peptide chemistry, small-molecule synthesis, screening technologies, biophysics and structural-molecular biology. As a collaborative CASE studentship with AstraZeneca, a research placement in Gothenburg will form part of the studentship. This will allow the design, synthesis and testing of candidate PPI stabilizers to discover selective and cell-permeable modulators.