Triazole-based STING inhibitors.

Aberrant activation of the DNA sensing cGAS-STING pathway has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus (SLE), and autoinflammatory disorders such as Aicardi-Goutières syndrome (AGS) and STING-associated vasculopathy with onset in infancy (SAVI). Consequently, considerable efforts have been directed toward the development of STING inhibitors. We previously reported that BB-Cl-amidine and LB244 inhibit STING-dependent signalling with nanomolar potency both in vitro and in vivo. The nitrofuran warhead on LB244 provided superior potency and proteome-wide selectivity. Moreover, LB244 mirrored the efficacy of BB-Cl-amidinein vivo. Herein, we describe the development of a series of triazole-based analogues designed to inhibit STING signalling. These efforts led to the development of ASF24, a highly potent inhibitor of STING signalling (IC50 = 0.49 μM). In summary, our findings identify a novel triazole-based STING inhibitor and establish a promising scaffold for the development of therapeutics targeting STING-mediated inflammatory diseases.