The discovery of potent small molecule cyclic urea activators of STING

STING mediates innate immune responses that are triggered by the presence of cytosolic DNA. Activation of STING to boost antigen recognition is a therapeutic modality that is currently being tested in cancer patients using nucleic-acid based macrocyclic STING ligands. We describe here the discovery of 3,4-dihydroquinazolin-2(1H)-one based 6,6-bicyclic heterocyclic agonists of human STING that activate all known human variants of STING with high potency. • Activation of STING is a highly promising approach in immunotherapy. • Optimised heterocyclic STING activators are based on a cyclic urea core. • The series potently activates all known human variants of STING and monkey STING. • An example potently induces release of inflammatory cytokines in PBMCs from monkeys. • An example has good drug-like properties and pharmacokinetics.