Background/Purpose: Cyclic GMP-AMP synthase (cGAS) is a nucleic acid sensor that plays a central role in anti-viral responses. Following the detection of intracellular double-stranded DNA, cGAS catalytically generates the dinucleotide 2’3’-cyclic GMP–AMP (cGAMP), which binds STING and triggers a signaling cascade that induces the expression of Type I interferons (IFN) and NF-kB mediated pro-inflammatory cytokines. While this response is important for effective anti-viral immunity, cGAS activation by aberrant cytoplasmic self-DNA, contributes to the immunopathology of diseases such as systemic lupus erythematosus (SLE), systemic sclerosis and dermatomyositis.

Methods: A high-throughput screen, in combination with structure-activity relationship studies and our proprietary computational platform (ReSOLVE^TM), identified a novel series of cGAS inhibitors. Biochemical activity was confirmed using cellular and whole blood assays prior to in vivo profiling in a Concanavalin A model of systemic inflammation. The efficacy of the cGAS inhibitors were assessed in a therapeutic dosing paradigm in the Trex1^-/- mouse model, a model that recapitulates multiple hallmarks of SLE including elevated Type I IFN activity, myocarditis, and photosensitivity.

Results: VENT-03 was identified as a novel selective cGAS inhibitor with excellent pharmacokinetic properties and robust pharmacodynamic activity in preclinical models. Tool molecules of the VENT-03 chemotype were efficacious in reducing auto-inflammation and rescuing clinically relevant endpoints in the Trex1^-/- mouse model. Specifically, cGAS inhibition led to a down modulation of IFN activity as well as expression of NF-kB driven pro-inflammatory mediators. Markers of cytotoxic CD8 activity were similarly reduced, suggesting that cGAS inhibition can impact the adaptive immune response in the context of complex inflammation. Notably, systemic inflammation was sufficiently suppressed to provide a survival benefit.

The impact of cGAS inhibition on dermal inflammation was also assessed in UVB-exposed Trex1^-/- mice as a model of photosensitivity. Following chronic UVB exposure, the low-grade dermal inflammation that is characteristic of Trex1^-/- mice is exacerbated and causes skin injury. In this model, cGAS inhibition reduced UVB-induced markers of dermal inflammation and improved skin integrity.

Aligned with these pre-clinical findings, activation of the cGAS-STING pathway was found to be heightened in SLE and CLE patients. Specifically, total and phosphorylated STING levels were found elevated in the skin of patients and these levels were further exacerbated by UVB exposure.   

Conclusion: VENT-03 is a first-in-class molecule with excellent drug-like properties that targets a central driver of autoinflammation, cGAS. We anticipate the inhibition of cGAS in humans by  VENT-03 will suppress multiple drivers of SLE pathology, including DNA-driven Type I IFN activity and NF-kB driven pro-inflammatory cytokines. VENT-03 therefore presents a unique therapeutic approach to the treatment of autoimmune diseases for which there remains a great unmet medical need. 

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/discovery-of-vent-03-a-novel-clinical-cgas-inhibitor-for-the-treatment-of-sle-and-other-autoimmune-diseases/