STING agonist C53

STING agonist C53 may be used: in promoting STING activation by binding to cryptic pocket in its transmembrane domain, enhancing oligomerization, immune signaling and in antitumor response.

STING agonist C53 (Compound 53), is a potent STING agonist with an EC50 of 185 nM for human STING activation. C53 modestly promotes STING oligomerization by binding to the transmembrane domain (TMD), acting orthogonally to cGAMP, which binds to the ligand-binding domain (LBD). In combination with cGAMP, C53 enhances STING activation (EC50 of 100 nM) and further promotes oligomerization, leading to stronger phosphorylation of STING, TANK-binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3) than either compound alone. Uniquely, C53 also inhibits STING′s proton channel activity in the Golgi, blocking processes such as microtubule-associated protein 1A/1B light chain 3 beta (LC3B) lipidation and nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome activation, while preserving its ability to induce interferon production. Although C53 activates human STING efficiently, it is inactive against mouse STING. In in vivo studies, C53 induces cytokine production and dendritic cell maturation, with increased expression of activation markers CD86 and CD83.