cGAS inhibitors (CD3)

Neuroinflammation has been widely accepted as a cause of the degenerative process. Increasing interest has been devoted to developing intervening therapeutics for preventing neuroinflammation in Parkinson's disease (PD). It is well known that virus infections, including DNA viruses, are associated with an increased risk of PD. In addition, damaged or dying dopaminergic neurons can release dsDNA during PD progression. However, the role of cGAS, a cytosolic dsDNA sensor, in PD progression remains unclear.

Adult male wild‐type mice and age‐matched male cGAS knockout (cGas−/−) mice were treated with MPTP to induce neurotoxic PD model, and then behavioral tests, immunohistochemistry, and ELISA were conducted to compare disease phenotype. Chimeric mice were reconstituted to explore the effects of cGAS deficiency in peripheral immune cells or CNS resident cells on MPTP‐induced toxicity. RNA sequencing was used to dissect the mechanistic role of microglial cGAS in MPTP‐induced toxicity. cGAS inhibitor administration was conducted to study whether GAS may serve as a therapeutic target.

We observed that the cGAS‐STING pathway was activated during neuroinflammation in MPTP mouse models of PD. cGAS deficiency in microglia, but not peripheral immune cells, controlled neuroinflammation and neurotoxicity induced by MPTP. Mechanistically, microglial cGAS ablation alleviated the neuronal dysfunction and inflammatory response in astrocytes and microglia by inhibiting antiviral inflammatory signaling. Additionally, the administration of cGAS inhibitors conferred the mice neuroprotection during MPTP exposure.

Collectively, these findings demonstrate microglial cGAS promote neuroinflammation and neurodegeneration during the progression of MPTP‐induced PD mouse models and suggest cGAS may serve as a therapeutic target for PD patients.

Although we demonstrated that cGAS promotes the progression of MPTP‐induced PD, this study has limitations. We identified that cGAS in microglia accelerate disease progression of PD by using bone marrow chimeric experiments and analyzing cGAS expression in CNS cells, but evidence would be more straightforward if conditional knockout mice were used. This study contributed to the knowledge of the role of the cGAS pathway in PD pathogenesis; nevertheless, trying more PD animal models in the future will help us to understand the disease progression deeper and explore possible treatments.

Cyclic GMP-AMP synthase (cGAS) has emerged as a promising therapeutic target of several human diseases, including Alzheimer’s disease (AD) and other neurodegenerative disorders. As a cytosolic DNA sensor, cGAS generates an innate immune response to promote neuroinflammation by producing an endogenous agonist of the stimulator of interferon genes (STING), 2’3’-cyclic GMP-AMP (cGAMP), which activates the cGAS–STING pathway. We have performed a high-throughput screening of a chemical library containing over 300K small molecules at the Fisher Drug Discovery Resource Center (DDRC), Rockefeller University (RU), to identify multiple hit inhibitors of human (h)-cGAS. We used a modified Kinase Glo® Luminescent Kinase assay, which was earlier developed at RU and later used by multiple groups, including ours, to perform primary screening of the library using h-cGAS. The hit candidates bearing novel scaffolds are structurally diverse and exhibited in vitro activity in the low micromolar range. RU-0610270 or compound (cpd) 1 , a sulfonamide derivative, is one of the most potent hits (IC 50 =1.88 µM), selected for hit expansion and structure-activity relationship (SAR) analysis. We synthesized new analogs of cpd 1 and evaluated them in vitro against h-cGAS to identify cpd 6 (IC 50 =0.66 µM) as the most potent hit analog. We further profiled cpd 6 and found that it modestly inhibited cGAMP levels by 29% at 30 µM in THP1 cells without detectable toxicity, and by 76% at 100 µM, albeit with a moderate decrease (∼20%) in cell viability. These results highlight a novel chemical series with promising in vitro activity, providing a starting point for the development of selective and potent human cGAS inhibitors for clinical use.