Developing innovative chemical tools to drive lytic cancer cell death

坏死性下垂是一种高度免疫原性的细胞死亡形式，由伪激酶MLKL.1的磷酸化和寡聚化触发。用能够寡聚或磷酸化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的治疗更敏感。为了实现这一目标，我们将首先设计、合成和验证能够与MLKL的ATP结合位点有效结合的化合物。这些将被详细阐述为诱导邻近化学工具3，它们介导MLKL的磷酸化、寡聚化或泛素化，这些化合物对坏死性下垂的影响将被调查。

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.