RU.521

cGAS inhibitor

RU.521 is described as a small molecule inhibitor of cGAS (cyclic GMP-AMP synthase, cGAMP synthase) [1,2].

In a healthy individual, cGAS senses the abnormal presence of cytosolic DNA such as during bacterial or viral infection. In some autoimmune diseases, cGAS can be constitutively activated by mislocalized self-DNA leading to high type I interferon (IFN) production. RU.521 has been demonstrated to reduce IFN production in vitro and in vivo in models of autoimmune disease, such as Aicardi-Goutières [1,2]. RU.521 more potently inhibits the activity of murine cGAS compared to human cGAS [2].

Read our review on cytosolic DNA sensors.

References:

1. Vincent J. et al., 2017. Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice. Nat Commun. 28(1):750.
2. Zhou W. et al., 2018. Structure of the human cGAS-DNA complex reveals enhanced control of immune surveillance. Cell. 174(2):300-311.

Figures

Effect of RU.521 on the response of RAW-Lucia™ ISG cells to cytosolic dsDNA. RAW-Lucia™ ISG cells were incubated with 1 μg/ml of cytosolic dsDNA (plasmid DNA delivered intracellularly using cationic lipid transfection) and increasing concentrations of RU.521. After overnight incubation, the IRF response was assessed by determining Lucia luciferase activity in the supernatant using QUANTI‑Luc™. Data are shown as percentages of the maximum response.

RU.521 primarily inhibits cGAS activity.
A: RAW-Lucia™ ISG cells were incubated with 1 μg/ml of cytosolic G3-YSD (Y-form DNA) and plasmid DNA in the presence or absence of 2.5 μg/ml of RU.521. G3-YSD and the plasmid DNA were delivered into the cytoplasm using cationic lipid transfection.
B: RAW‑Lucia™ ISG-KO-cGAS cells were incubated with 10 μg/ml of 2’3’-cGAMP in the presence or absence of 2.5 μg/ml of RU.521. After overnight incubation, the IRF response was assessed using QUANTI‑Luc™ and expressed as percentages of the maximum response.

Specifications

Working concentration: 200 ng/ml (482 nM) to 20 μg/ml (48.2 μM) for cell culture assays.

Solubility: 5 mg/ml (12.05 mM) in DMSO

Formula: C₁₉H₁₂Cl₂N₄O₃

Molecular weight: 415.23 g/mol

Quality control:

• Purity ≥ 95% (UHPLC).
• The absence of bacterial contamination (e.g. lipoproteins and endotoxins) has been confirmed using HEK-Blue™ TLR2 and HEK‑Blue™ TLR4 cells.
• The inhibitory activity has been validated using cellular assays.

Contents

• 2 mg RU.521

RU.521 is shipped at room temperature.

Store at -20°C.

Resuspended product is stable for at least 6 months when properly stored.