Design, Synthesis, and Biological Evaluation of Selective STING Synergists That Enhance cGAMP-STING Pathway Activation without Inherent Agonist Activity

The cGAS-STING pathway is pivotal for innate immunity and antitumor responses. However, the challenge of selectively targeting the diseased tissue without harming the healthy tissue has impeded the development of STING agonists. In this article, we tackle this issue by developing novel STING synergists that target the STING C-terminal domain pocket. Our findings indicate that agonist 12B can boost the cGAMP-STING pathway synergistically. Through reverse optimization of 12B, we synthesized three series of compounds, with compounds 55, 66, and 67 emerging as selective STING synergists that amplify cGAMP-induced pathway activation without inherent agonist properties. Compound 67 emerged as the most potent (EC₅₀ = 20.53 μM), displaying a broad binding affinity across STING-CTD alleles and potent antitumor efficacy in vivo. Notably, it exhibited excellent safety profiles in both in vitro and in vivo models, along with favorable pharmacokinetics. These findings highlight the therapeutic potential of novel STING synergists for cancer immunotherapy.