Synthesis and Evaluation of Targeted Covalent Enzyme Inhibitors in Cancer

癌症靶向共价酶抑制剂的合成和评价

• 批准号: 2284252
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2284252
• 关键词: Synthesis; Evaluation; Targeted; Covalent; Enzyme

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.

该职位将于 2019 年 10 月开始在南安普顿大学化学学院 Matthias Baud 博士的监督下工作。该项目将处于化学和生物科学的交叉点，并将重点开发新型温和共价试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 (TCIs) 是含有反应性化学“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药物发现的一个快速增长的领域。通过允许反应弹头与蛋白质的特定位点共价、不可逆地结合，这是提高小分子抑制剂的效力和/或选择性的有效方法。该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，以及使用内部体外测定评估其生物活性。我们对这些方法的应用特别感兴趣：1）提高抑制剂对结构相关蛋白的选择性，2）同时解决源自癌症突变的耐药性这一挑战性问题。