MSA-2 is an orally available non-nucleotide STING agonist with antitumor activity. MSA-2 shows EC50s of 8.3 and 24 μM for human STING isoforms WT and HAQ, respectively. MSA-2 induces tumor regression with durable antitumor immunity, and synergizes with anti-PD-1 in syngeneic mouse tumor models. MSA-2 dosed via either PO or SC regimens achieved comparable exposure in both tumor and plasma. MSA-2 also exhibits dose-dependent antitumor activity when administered by IT, SC, or PO routes, and dosing regimens were identified that induced complete tumor regressions in 80 to 100% of treated animals. In tumor models that are moderately or poorly responsive to PD-1 blockade, combinations of MSA-2 and anti-PD-1 antibody are superior in inhibiting tumor growth and prolonging survival over monotherapy.
Cancer Lett. 2023 Oct 1;573:216370.
Low-dose metronomic chemotherapy triggers oxidized mtDNA sensing inside tumor cells to potentiate CD8+ T anti-tumor immunity
MSA-2 purchased from AbMole
| Cell Experiment | |
|---|---|
| Cell lines | THP-1 cells, mouse macrophages |
| Preparation method | In the primary screen, THP-1 cells are incubated, in 1536-well plates, with test compounds (20 μM) in a RPMI1640-based assay medium in the presence of 5% carbon dioxide at 37°C for 5 hours. IFN-b levels are determined using an AlphaLISA assay and an EnVision Reader and expressed as percentages of IFN-b induced by cGAMP. STING binding activity of compounds is evaluated with a competitive radioligand binding assay using tritiated cGAMP and membrane embedded full-length recombinant human and mouse STING generated in insect cells. STING pathway activation by MSA-2 is assessed by Western blotting, probing phosphorylation status and total protein levels of STING, TBK-1, and IRF3 by using commercially available antibodies. |
| Concentrations | 20 μM, 0.16 μM-100 μM |
| Incubation time | 5 h |
| Animal Experiment | |
|---|---|
| Animal models | C57BL/6J mice, NSG mice, BALB/c mice, nude NCr mice |
| Formulation | - |
| Dosages | 25 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 80 mg/kg, 160 mg/kg |
| Administration | intra tumor injection, SC, PO |
| Molecular Weight | 294.32 |
| Formula | C14H14O5S |
| CAS Number | 129425-81-6 |
| Solubility (25°C) | DMSO ≥ 40 mg/mL |
| Storage | 2-8°C, protect from light, sealed |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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