Discovery of an Orally Bioavailable STING Inhibitor with In Vivo Anti-Inflammatory Activity in Mice with STING-Mediated Inflammation

The cyclic GMP-AMP synthase (cGAS)-stimulator of the
interferon
genes (STING) pathway plays a key role in triggering interferon and
inflammatory responses against microbial invasion or tumor. However,
aberrant activation of the cGAS-STING pathway is associated with a
variety of inflammatory and autoimmune diseases, and thus inhibition
of STING is regarded as a potential new approach to treating these
diseases. Herein, we report a series of novel indolyl-urea derivatives
as STING inhibitors. The representative compound 42 exhibited
potent STING inhibitory activity, acceptable pharmacokinetic properties,
and good in vivo safety profiles. Mechanistically, 42 could block the palmitoylation of the STING protein and STING downstream
signaling. Importantly, oral administration of 42 could
effectively suppress STING-mediated inflammation in 10-carboxymethyl-9-acridanone
(CMA)-treated mouse and Trex1–/– mouse. Together, compound 42 represents a promising
STING inhibitor for treating STING-associated inflammatory and autoimmune
diseases.

环GMP-AMP合酶（cyclic GMP-AMP synthase, cGAS）-干扰素基因刺激因子（stimulator of interferon genes, STING）通路在触发针对微生物入侵或肿瘤的干扰素与炎症应答中发挥关键作用。然而，cGAS-STING通路的异常激活与多种炎症性及自身免疫性疾病相关，因此抑制STING被视为治疗此类疾病的潜在新策略。本文报道了一系列新型吲哚基脲类STING抑制剂。代表性化合物42展现出强效的STING抑制活性、良好的药代动力学特性与理想的体内安全性特征。机制研究表明，化合物42可阻断STING蛋白的棕榈酰化修饰及其下游信号通路。值得注意的是，经口服给予化合物42，可有效抑制10-羧甲基-9-吖啶酮（10-carboxymethyl-9-acridanone, CMA）处理小鼠与Trex1基因敲除（Trex1–/–）小鼠体内STING介导的炎症反应。综上，化合物42是一款极具开发前景的STING抑制剂，有望用于治疗STING相关的炎症性与自身免疫性疾病。