Design of an Oral STING Agonist through Intramolecular Hydrogen Bond Ring Mimicking to Achieve Complete Tumor Regression

Stimulator of interferon genes (STING) is a promising
target for
cancer immunotherapy. However, current development of STING agonist
was limited by poor therapeutic efficacy. Herein, we designed potent
oral STING agonists through intramolecular hydrogen bond ring mimicking
strategy. Structure optimization identified lead compound ZSA-215
with potent cellular STING-stimulating activity. ZSA-215 enhanced
STING signaling through promoting the phosphorylation of STING and
interferon regulatory factor 3 (IRF3) and secretion of IFN-β.
Notably, monotherapy of oral ZSA-215 achieved complete tumor regression
and long-term survival of mice in MC38 colon cancer model, which is
superior to MSA-2. Furthermore, ZSA-215 exhibited excellent metabolic
and chemical stability in vitro, high oral drug exposure (AUC = 23835.0
h·ng/mL) and bioavailability (F = 58%). These
results suggest that ZSA-215 is a potent oral STING agonist warrant
further development for cancer immunotherapy.