Taking the STING out of it: novel chemical tools to dissect cancer signalling

In this interdisciplinary project, you will develop novel chemical tools to study an important cancer signalling pathway. The project is ideally suited for applicants with an interest and experience in medicinal/organic chemistry, who want to expand their skills in organic synthesis, and learn new experimental techniques e.g., in cell biology. 

The STING (stimulator of interferon genes) signalling cascade is a recently discovered pathway with a unique role in innate immunity. STING signalling controls interferon-β (IFN-β) secretion, and aberrant activation of this pathway has been linked directly to serious disorders, including cancer, autoimmune disorders, and inflammatory conditions. Although the STING pathway has attracted considerable attention as a novel therapeutic target, the molecular mechanisms of this pathway are far from fully understood. 

The central component of the STING pathway is the adaptor protein STING. The main endogenous ligand of STING is the non-canonical cyclic dinucleotide cGAMP (cyclic GMP-AMP), but other second messengers are also recognised as ligands. Upon ligand binding, STING is activated via a complex mechanism, details of which appear to be ligand- and species-dependent. Clinically relevant single point mutations that affect STING activation have also been described. 

The goal of this interdisciplinary project is the development of novel analogues and mimics of cGAMP to elucidate the mechanistic details of STING activation including the impact of clinically relevant mutations and to study STING signalling in cells. Project outcomes will provide important new insights into this unique signalling pathway and enable the development of novel therapeutics for cancer and inflammatory diseases.