Developing innovative chemical tools to drive lytic cancer cell death

开发创新化学工具来驱动溶解性癌细胞死亡

• 批准号: 2868982
• 金额: --
• 依托单位: Institute of Cancer Research
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2868982
• 关键词: Developing; innovative; chemical; tools; drive

Necroptosis is a highly immunogenic form of cell death, and is triggered by phosphorylation and oligomerisation of the pseudokinase MLKL.1 Activating this process with molecules which can oligomerise or phosphorylate MLKL has the potential to make tumours more responsive to treatment with immune checkpoint inhibitors. To accomplish this, we will first design, synthesise and validate compounds capable of binding potently to the ATP-binding site of MLKL. These will be elaborated into induced-proximity chemical tools3 which mediate phosphorylation, oligomerisation or ubiquitylation of MLKL, and the effect of these compounds on necroptosis will be investigated.

坏死性凋亡是一种高度免疫原性的细胞死亡形式，由假激酶MLKL的磷酸化和寡聚化引发。1用可以寡聚化或磷酸化MLKL的分子激活这一过程有可能使肿瘤对免疫检查点抑制剂治疗更具反应性。为了实现这一目标，我们将首先设计，合成和验证能够有效结合MLKL的ATP结合位点的化合物。这些将被详细阐述为介导MLKL磷酸化、寡聚化或泛素化的诱导邻近化学工具3，并将研究这些化合物对坏死性凋亡的影响。