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

瞬时蛋白质-蛋白质相互作用（PPI）控制着与健康和疾病相关的所有细胞过程。因此，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控。P53通过与hDM 2和/或hDMX的相互作用而负调控。这些蛋白质调节p53的定位，物理地阻断其与DNA的相互作用，并协同作用以通过泛素化和随后的蛋白水解降解来实现p53降解。1 -3反过来，hDM 2和hDMX功能通过与衔接蛋白的磷酸化依赖性相互作用来调节14-3-3.4-5鉴于hDM 2和hDMX在许多癌症中过表达，p53/hDM 2（X）相互作用作为药物发现靶点已经受到相当大的关注。6本博士项目将通过鉴定和优化hDM 2/14-3-3和hDMX/14-3-3的稳定剂来寻求靶向致癌p53通路的替代方法。该项目将利用我们的工具包，使药物发现能力，7-8内部晶体学和生物物理学数据的性质，hDM 2/14-3-3和hDMX/14-3-3相互作用，以及击中物质确定从传统的筛选和动态片段连接实验。将采用一系列适合于目标的方法，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学生奖学金，哥德堡的研究实习将成为学生奖学金的一部分。这将允许候选PPI稳定剂的设计、合成和测试，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.1-3 In turn hDM2 and hDMX function is regulated through phosphorylation dependent interaction with the adaptor protein 14-3-3.4-5 Given that hDM2 and hDMX are overexpressed in numerous cancers, the p53/hDM2(X) interaction has received considerable attention as a drug-discovery target.6This 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,7-8 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 a selective and cell-permeable modulators.