Discovery of Non-Nucleotide Small-Molecule STING Agonists via Chemotype Hybridization

The identification of agonists of the stimulator of interferon genes (STING) pathway has been an area of intense research due to their potential to enhance innate immune response and tumor immunogenicity in the context of immuno-oncology therapy. Initial efforts to identify STING agonists focused on the modification of 2′,3′-cGAMP (1) (an endogenous STING activator ligand) and other closely related cyclic dinucleotides (CDNs). While these efforts have successfully identified novel CDNs that have progressed into the clinic, their utility is currently limited to patients with solid tumors that STING agonists can be delivered to intratumorally. Herein, we report the discovery of a unique class of non-nucleotide small-molecule STING agonists that demonstrate antitumor activity when dosed intratumorally in a syngeneic mouse model.鉴于在肿瘤免疫治疗背景下，干扰素基因刺激因子（STING）通路激动剂具备增强先天免疫应答与肿瘤免疫原性的潜力，针对该类激动剂的识别一直是研究热点领域。早期筛选STING激动剂的工作主要聚焦于对2′,3′-环鸟苷单磷酸（2′,3′-cGAMP，1）——一种内源性STING激活配体——以及其他密切相关的环二核苷酸（CDNs）进行修饰改造。尽管此类研究已成功发现多款已进入临床阶段的新型环二核苷酸类激动剂，但目前其应用范围仅局限于可通过瘤内给药的实体瘤患者。本文报道了一类独特的非核苷酸类小分子STING激动剂，该类化合物在同基因小鼠模型中经瘤内给药后可展现出明确的抗肿瘤活性。