monomers are positioned to form hydrogen-
bond interactions with both the carboxylic
acid of one bound molecule of SR-717 and the
amide carbonyl of the other bound SR-717
molecule (Fig. 2D and fig. S9B). These side
chains, at the base of the cGAMP binding site,
form hydrogen-bonding interactions with the
purine bases of bound cGAMP (PDB ID 4KSY).Consistent with the observed requisite of a
carboxylic acid for binding (fig. S2E), the car-
boxylic acid of each molecule of bound SR-717
is directly positioned in the location of aChinet al.,Science 369 , 993–999 (2020) 21 August 2020 4of7
B16F.10 (5e^5 cells)
Day 1Day 11
Treat daily for 7 days
30 mg / kg I.P.C5 mg/kg15 mg/kg30 mg/kg0100200300400500600
A BIFN-β (pg/mL)IFN-β
IL-6Cytokine (pg/mL)
020040060080010001200Vehicle SR-717 Vehicle SR-717
WT Stinggt/gtVehicle SR-717 DMXAA0306090120150# of nodules / set of lungs**
n.d.Time post B16.F10 injection (days)15 18 21 24 27 300255075100Time post B16.F10 injection (days)Survival (%)WT + vehicle
WT + SR-717
Stinggt/gt + vehicle
Stinggt/gt +SR-717WT + vehicle
WT + SR-717
Stinggt/gt +vehicle
Stinggt/gt + SR-717D E FVehicle
SR-717
Anti-PD-1
Anti-PD-1 + SR-717G H IVehicle
SR-717
Anti-PD-L1
Anti-PD-L1 + SR-717JK10 15 20 25 30 350255075100Survival (%)Vehicle
SR-717
Anti-PD-L1
Anti-PD-L1 + SR-71710 15 20 25 30 350255075100Survival (%)Vehicle
SR-717
Anti-PD-1
Anti-PD-1 + SR-717VehicleSR-717DMXAA10 12 14 16 18 20
05001000150020002500Tumor volume (mm3 )Treatment10 12 14 16 18 20030060090012001500Time post B16.F10 injection (days)Tumor volume (mm3 )Time post B16.F10 injection (days)Time post B16.F10 injection (days)10 12 14 16 18 20030060090012001500Time post B16.F10 injection (days)Tumor volume (mm3 )Fig. 3. STING-dependent pharmacodynamic and antitumor activities of
systemic SR-717.(A) Dose escalation of SR-717 by intraperitoneal injection and
corresponding plasma IFN-blevels in C57BL/6 mice (n= 4) 4 hours after dosing,
after 4 days of daily dosing (n= 4). (B) Plasma concentrations of cGAS-STING
signaling target cytokines after dosing with SR-717 (15 mg/kg intraperitoneally)
in WT (n=4)orStinggt/gtmice (n= 4). (C) Schematic of therapeutic
treatment strategy of B16.F10 tumor-bearing mice used to evaluate SR-717.
I.P., intraperitoneal. (D) Impact of SR-717 [30 mg/kg intraperitoneally, using
dosing regimen described in (C)] on B16.F10 tumor growth in WT (n=8)or
Stinggt/gtmice (n= 8). (E) Kaplan-Myer survival curve of WT (n=8)or
Stinggt/gtB16.F10 tumor-bearing mice (n= 8) after treatment with SR-717 as
described in (D). Mice were euthanized when tumor area exceeded 2000 mm^3.
(F) Impact of SR-717 or DMXAA positive control (both dosed at 15 mg/kg
intraperitoneally, once per day) on metastasized B16.F10 lung nodule formation
in C57BL/6 mice. Pulmonary nodules were quantified 7 days after intravenous
tail vein administration of B16.F10 cells (n= 5 mice for vehicle,n= 5 for SR-717,
andn= 3 for DMXAA). Each data point represents the number of nodules per set
of lungs in each mouse. **P≤0.01; n.d., no difference. (G) Representative
images of isolated lungs from studies described in (F). (H) Impact of SR-717
[n= 8, 30 mg/kg intraperitoneally, using dosing regimen described in (C)
starting on day 10]; anti-PD-1 antibody (n= 8, 200mg on days 10, 14, and 17);
or combination SR-717 plus anti–PD-1 treatment (n= 8) on B16F.10 tumor
growth in WT C57BL/6 mice. (I) Kaplan-Myer survival curve of WT B16.F10
tumor-bearing mice (n= 8) after treatments described in (H). (J) Impact of
SR-717 [30 mg/kg intraperitoneally, using dosing regimen described in (C)
starting on day 11] (n= 8); anti-PDL1 antibody (200mg on days 11, 14, and 17)
(n= 8); or combination thereof (n= 8) on B16F.10 tumor growth in WT C57BL/6
mice. (K) Kaplan-Myer survival curve of WT B16.F10 tumor-bearing mice (n=8)
after treatments described in (J). Data are representative of three independent
experiments, and values are the mean ± SEM [(A), (B), and (D) to (K)].RESEARCH | REPORT