Synthesis and Evaluation of Targeted Covalent Enzyme Inhibitors in Cancer

这一职位将于2019年10月开始，在南安普顿大学化学学院马蒂亚斯·波特博士的监督下工作。该项目将处于化学和生物科学的交界处，并将专注于开发新型温和的共价剂作为抑制剂或一系列备受瞩目的疾病驱动蛋白。靶向共价抑制物(TCI)是一种含有活性化学“弹头”的蛋白质配体，能够与蛋白质靶标产生共价键。对关键疾病相关蛋白的靶向共价抑制是药物发现中一个快速增长的领域。通过允许反应性弹头与蛋白质的特定位置发生共价、不可逆的结合，这是提高小分子抑制剂效力和/或选择性的有效方法。候选人将专注于我们实验室目前正在研究的新型温和反应弹头功能化TCI的设计和合成，以及使用内部体外分析对其生物活性进行评估。我们特别感兴趣的是这些方法的应用：1)提高抑制剂在结构相关蛋白质中的选择性；2)解决由癌症突变引起的抗药性这一具有挑战性的问题。

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.