Synthesis and Evaluation of Targeted Covalent Enzyme Inhibitors in Cancer

该职位将于2019年10月开始，在南安普顿大学化学学院Matthias Baud博士的指导下工作。该项目将在化学和生物科学的界面，并将侧重于开发新型的温和共价剂作为抑制剂或一系列备受瞩目的疾病驱动蛋白。靶向共价抑制剂（tci）是一种含有活性化学“弹头”的蛋白质配体，能够与蛋白质靶标形成共价键。关键疾病相关蛋白的靶向共价抑制是一个快速发展的药物发现领域。通过允许反应弹头与蛋白质的特定位点进行共价、不可逆的结合，这是一种增强小分子抑制剂效力和/或选择性的有力方法。该候选人将专注于设计和合成使用我们实验室正在研究的新型轻度反应弹头功能化的tci，以及使用内部体外分析评估其生物活性。我们对这些方法的应用特别感兴趣：1)提高抑制剂在结构相关蛋白上的选择性；2)以及解决癌症突变引起的耐药性的挑战性问题。

This position will start in October 2019 to work under the supervision of Dr Matthias Baud in the School of Chemistry at the University of Southampton. This project will be at the interface of the chemical and biological sciences, and will focus on the development of new types of mild covalent agents as inhibitors or a range of high-profile disease driving proteins. Targeted covalent Inhibitors (TCIs) are protein ligands containing a reactive chemical "warhead" able to create a covalent bond with the protein target. Targeted covalent inhibition of key disease associated proteins is a rapidly growing area of drug discovery. It is a powerful way to increase the potency and/or selectivity of small molecule inhibitors by allowing the covalent, irreversible association of a reactive warhead to specific sites of proteins. The candidate will focus on the design and synthesis of TCIs functionalised with new types of mild reactive warheads currently under investigation in our laboratory, along with the evaluation of their bioactivity using in-house in vitro assays. We are particularly interested in the application of these methodologies for 1) improving the selectivity profile of inhibitors across structurally related proteins, 2) along with addressing the challenging issues of drug resistance originating from mutations in cancer.