Specific inhibitor of human cGAS

Inhibition of human cGAS signaling by G140

G140 is a small-molecule inhibitor of human cGAS (cyclic GMP-AMP synthase; cGAMP synthase). cGAS is the primary sensor of cytosolic double-stranded DNA (dsDNA) originating either from pathogenic infections, mitochondrial dsDNA misprocessing, or micronuclei rupture. Direct DNA binding to cGAS catalyzes the production of 2', 3'-cGAMP, a cyclic dinucleotide, which in turn activates the STING pathway, resulting in IRF (interferon regulatory factor) and NF‑κB-mediated expression of pro-inflammatory cytokine and type-I interferons [2-4].
G140 is a promising probe for the development of drugs targeting human cGAS for preventing auto-inflammation and treating interferonopathies [5]. G140 was co-developed along with another chemotype, G150, and both molecules display similar potency at inhibiting cGAS [1].
More details

Mode of action:

Co-crystallization studies with another lead compound, G150, revealed that the small molecule targets the human cGAS catalytic pocket, competing with cGAS substrates ATP/GTP, thereby inhibiting the synthesis of 2', 3'-cGAMP [1, 4].

Key features:

Potent and selective inhibitor of human cGAS
No substantial cellular toxicity [1]
Inhibition of IRF and NF-κB signaling validated in cellular assays
InvitroFit™ grade: each lot is highly pure (≥95%) and functionally tested

Note: InvivoGen also offers RU.521, a specific inhibitor of murine cGAS.

References:

1. Lama, L. et al., 2019. Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression. Nat Commun 10, 2261.
2. Gao, D. et al., 2015. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. PNAS 112, E5699-5705.
3. Abe, T. et al., 2014. Cytosolic-DNA-mediated, STINGdependent proinflammatory gene induction necessitates canonical NF-kappaB activation through TBK1. J Virol 88, 5328-5341.
4. Hertzog, J. & Rehwinkel J., 2020. Regulation and inhibition of the DNA sensor cGAS. EMBO Reports 21(12):e51345.
5. Tan J. et al., 2021. Synthesis and pharmacological evaluation of Tetrahydro-γ-carboline derivatives as potent anti-inflammatory agents targeting cyclic GMP-AMP synthase. J. Med Chem. 64(11):7667-7690.

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