Discovery of 3,4-dihydroisoquinoline-2(1H)-carboxamide STING inhibitors as anti-inflammatory agents

Stimulator of interferon genes (STING) is an endoplasmic reticulum-localized adaptor protein that plays a vital role in mediating the cytosolic DNA-sensing pathway to prime the innate immune responses. Overactivated STING axis causes excessive accumulation of interferons and proinflammatory cytokines, leading to autoimmune and autoinflammatory diseases such as STING-associated vasculopathy of infancy (SAVI) and Aicardi-Goutières syndrome (AGS). Inhibiting the aberrant STING signaling with its inhibitors has proven to alleviate the inflammatory symptoms of the autoimmune and autoinflammatory diseases. Here we report the discovery of 3,4-dihydroisoquinoline-2(1H)-carboxamide STING inhibitors. Extensive structure-activity relationship (SAR) study allowed us to identify compound 5c with cellular human- and mouse-STING inhibitory IC₅₀ values of 44 and 32 nM, respectively. It effectively inhibited the activation of the STING axis in both human and murine cells, potentially through covalent binding to the transmembrane domain of STING. Compound 5c also demonstrated robust in vivo anti-inflammatory efficacy on STING agonist-stimulated systemic inflammation and cisplatin-induced acute kidney injury (AKI) mice models. Further study revealed that 5c could restore renal mitochondrial function, suppress reactive oxygen species production, and reduce cell apoptosis to protect mice against cisplatin-induced AKI.