Stimulator of Interferon Genes (STING) is essential for the inflammatory response to cytosolic DNA. Despite that aberrant activation of STING is linked to an increasing number of inflammatory diseases, the development of inhibitors has been challenging, with no compounds in the pipeline beyond the preclinical stage. We previously identified endogenous nitrated fatty acids as novel reversible STING inhibitors. With the aim of improving the specificity and efficacy of these compounds, we developed and tested a library of nitroalkene-based compounds for and STING inhibition. The structure-activity relationship study revealed a robustly improved electrophilicity and reduced degrees of freedom of nitroalkenes by conjugation with an aromatic moiety. The lead compounds CP-36 and CP-45, featuring a β-nitrostyrene moiety, potently inhibited STING activity and relieved STING-dependent inflammation This validates the potential for nitroalkene compounds as drug candidates for STING modulation to treat STING-driven inflammatory diseases, providing new robust leads for preclinical development.

中文翻译：

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开发基于硝基烯烃的抑制剂来靶向 STING 依赖性炎症


干扰素基因刺激物 (STING) 对于细胞质 DNA 的炎症反应至关重要。尽管 STING 的异常激活与越来越多的炎症性疾病有关，但抑制剂的开发一直具有挑战性，目前尚未有任何化合物处于临床前阶段。我们之前将内源性硝化脂肪酸鉴定为新型可逆 STING 抑制剂。为了提高这些化合物的特异性和功效，我们开发并测试了用于抑制 STING 的基于硝基烯烃的化合物库。结构-活性关系研究表明，通过与芳香族部分缀合，硝基烯烃的亲电性得到了显着提高，自由度降低了。先导化合物 CP-36 和 CP-45 具有 β-硝基苯乙烯部分，可有效抑制 STING 活性并缓解 STING 依赖性炎症。这验证了硝基烯烃化合物作为 STING 调节候选药物治疗 STING 驱动的炎症性疾病的潜力，提供用于临床前开发的新的强有力的先导化合物。