Discovery of a potent and orally bioavailable 3,3-dimethyl-2-oxoindoline STING inhibitor

Stimulator of interferon genes (STING) plays an imperative role in the innate immune response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Overstimulated STING axis has proven to incur multiple autoimmune or inflammatory diseases, such as Aicardi-Goutières syndrome, systematic lupus erythematosus, and amyotrophic lateral sclerosis. Here we report the discovery of a series of 3,3-dimethyl-2-oxoindoline STING inhibitors. We converted the STING agonist G10 to a STING inhibitor 8a by grafting an indole-3-yl group, and extensive structure-activity relationship (SAR) exploration of 8a allowed us to identify compound 10a as a potent and orally bioavailable STING inhibitor. Biological characterization unraveled that 10a significantly suppressed the STING signaling pathway in human monocytes and murine macrophages, potently alleviated cisplatin-induced kidney injury both in vitro and in vivo, as well as achieved robust anti-inflammatory efficacy on STING agonist-induced inflammation mice model through systemic administration. The proposed binding mode of 10a and the STING protein displays that 10a targets the transmembrane domain of STING.