Rational design of carbazole-based STING inhibitors for treating cGAS-STING pathway-driven inflammatory disorders.

Area of Science:

• Immunology
• Pharmacology
• Structural Biology

Background:

• The Stimulator of Interferon Genes (STING) protein is crucial in innate immunity, but its dysregulation drives autoimmune diseases.
• Existing STING inhibitors present challenges like off-target toxicity and unclear binding mechanisms, necessitating new therapeutic strategies.

Purpose of the Study:

• To identify and characterize novel STING inhibitors with improved properties.
• To explore the therapeutic potential of these inhibitors in preclinical models of autoimmune conditions.

Main Methods:

• Utilized target and cell-based cascade screening combined with rational drug design to discover DDO-88109.
• Determined inhibitor potency (IC50 values) and selectivity across human STING isoforms.
• Investigated the binding mechanism using co-crystal structure analysis.
• Evaluated efficacy in mouse models of TREX1 deficiency-induced autoinflammation and cisplatin-induced acute kidney injury (AKI).

Main Results:

• Identified DDO-88109, a carbazole derivative, as a potent STING inhibitor with IC50 values in the low micromolar range.
• DDO-88109 demonstrated broad affinity for human STING variants and effectively suppressed the cGAS-STING pathway.
• Co-crystal structure revealed a 2:1 binding stoichiometry within the CDN-binding pocket of STING.
• In vivo studies showed DDO-88109 significantly reduced inflammatory factors and ameliorated tissue damage in disease models.

Conclusions:

• DDO-88109 represents a promising small-molecule STING inhibitor developed through structure-based rational design.
• This compound effectively targets the cGAS-STING pathway, showing therapeutic potential for autoimmune diseases.
• The findings establish a framework for developing STING inhibitors for human autoimmune disorders.