Background/Purpose: The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a key innate immune mediator of autoimmune and inflammatory diseases. However, the development of a drug-like STING antagonist remains challenging. Here, we report the discovery and characterization of RGT-118, a highly potent, selective and orally bioavailable small molecule STING antagonist for autoimmune disorders in preclinical models.

Methods: By leveraging the Computer Accelerated Rational Design (rCARD^TM) platform, we designed and synthesized a small molecule STING antagonist RGT-118. Cellular potency was measured in cGAMP stimulated THP-1 cells with IFN-b secretion as a readout. The absorption (MDCK based permeability assay and kinetic solubility), distribution (free fraction in plasma), and metabolism (liver microsomes, hepatocytes, plasma and blood stability) were characterized in in vitro assays. The pharmacokinetic (PK) study was performed in preclinical species to evaluate the exposure and bioavailability. Proof-of-mechanism (POM) studies were also performed using a mouse model in which the inhibition of RGT-118 on the production of IFN-a, IFN-b, IL-6 and TNF-a was measured after being challenged with cGAMP. Trex1^-/- mouse model was used to investigate the mechanistic activity of RGT-118. In addition, imiquimod-induced psoriasis model was used to evaluate the efficacy of RGT-118 in inhibiting disease development. Furthermore, to explore the therapeutic window of RGT-118, rat and dog 14-day dose-range finding (DRF) exploratory toxicity studies were performed.

Results: RGT-118 covalently binds to cysteine residue 91 in transmembrane domain, which blocks the activation induced palmitoylation of STING. The downstream pathways (i.e. type I IFN and NF-kB) mediated by cGAS-STING were attenuated by RGT-118 in a dose-dependent manner in both cellular assay and in vivo POM study. RGT-118 demonstrated good permeability and solubility in vitro. Furthermore, it showed good oral bioavailability and drug exposure in vivo in rat and dog. In Trex1^-/- mice, treatment of RGT-118 significantly increased body weight and decreased ISGs and NF-kB related cytokines. Additionally, it showed comparable therapeutic effect in IMQ-induced psoriasis model with head-to-head comparison of PDE4i and anti-IL-17 treatment. Moreover, no severe toxicological signs were observed in both rat and dog 14-day dose-range finding studies and the no-observed-adverse-effect-level (NOAEL) of this compound was determined to be 200 mg/kg/day.

Conclusion: RGT-118 is a highly potent, selective and orally bioavailable small molecule STING antagonist with demonstrated efficacy in several preclinical animal models. With a favorable therapeutic window, RGT-118 provides therapeutic opportunities in multiple autoimmune and inflammatory diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/autoimmune-pathway-blockade-by-a-potent-orally-bioavailable-sting-antagonist/