SR-717 is a non-nucleotide STING agonist with EC50s of 2.1 μM and 2.2 μM in ISG-THP1 (WT) and ISG-THP1 cGAS KO (cGAS KO) cell lines, respectively. Antitumor activity .
Stimulator of interferon genes (STING) is an endoplasmic reticulum signaling protein which has been demonstrated to play essential roles in antitumor immunity. SR-717 is a non-nucleotide, small-molecule STING agonist with an IC50 of 7.8 μM. Within the CD45.2+ population, SR-717 treatment resulted in a significant increase in the frequency of CD8 T cells among TILs (tumor infiltrating lymphocytes) and a decrease in the frequencies of NK cells within the draining lymphnode (dLN) and spleen. In WT C57BL/6 mice, SR-717 induced IFN-β after intraperitoneal administration in a dose-dependent manner. In WT or Stinggt/gt mice, a 30 mg/kg intraperitoneal once-per-day regimen of SR-717 for 1 week was found to maximally inhibit B16.F10 tumor growth. In C57BL/6 mice bearing B16.F10 cells, SR-717 (15 mg/kg; dosed intraperitoneally; once per day) significantly inhibited the formation of pulmonary nodules in this model of metastasis. SR-717 (30 mg/kg intraperitoneally) displayed a better level of efficacy than anti-PD-1 or anti-PD-L1 antibody therapy on reducing tumor burden and improving overall survival in the B16.F10 model[2].
作用机制
The structure of SR-717 facilitates a binding mode in which Thr263 side chain hydroxyls from both monomers are positioned to form hydrogen-bond interactions with SR-717[2].
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