Developing innovative chemical tools to drive lytic cancer cell death

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.