Rational design of carbazole-based STING inhibitors for treating cGAS-STING pathway-driven inflammatory disorders - PubMed
6 hours ago
- #inflammatory disorders
- #STING inhibitors
- #carbazole-based
- STING is a key adaptor protein in innate immunity, linked to autoimmune diseases.
- Current STING inhibitors have issues like off-target toxicity and unclear binding mechanisms.
- DDO-88109, a carbazole-based STING inhibitor, was identified with IC50 values of 1.76 μM (THP1-Dual) and 1.85 μM (RAW-Lucia ISG).
- It binds to multiple hSTING isoforms and selectively inhibits the cGAS-STING pathway.
- Co-crystal structure shows DDO-88109 occupies the CDN-binding pocket of STING in a 2:1 stoichiometry.
- In mouse models (TREX1 deficiency, cisplatin-induced AKI), DDO-88109 reduces inflammation and improves tissue health at 15 mg/kg.
- The discovery provides a structure-based development paradigm for STING inhibitors against autoimmune diseases.
- Patent (CN 117800898 A) covers synthesis and use of carbazole-based STING inhibitors for treating autoimmune disorders.