An orally available non-nucleotide STING agonist with antitumor activity

• DOI: 10.1126/science.aba6098
• Publication Date: 2020-12-02T18:22:22Z
• Authors: Bo-Sheng Pan; Samanthi A. Perera; Jennifer A. Piesvaux; Jeremy P. Presland; Gottfried K. Schr...; Jared N. Cumming; B. Wesley Trotter; Michael D. Altman; Alexei V. Buevich; Brandon Cash; Saso Cemerski; Wonsuk Chang; Yiping Chen; Peter J. Dandliker; Guo Feng; Andrew Haidle; Timothy Henderson; James Jewell; Ilona Kariv; Ian Knemeyer; Johnny Kopinja; Brian M. Lacey; Jason Laskey; Charles A. Lesburg; Rui Liang; Brian J. Long; Min Lu; Yanhong Ma; Ellen C. Minnihan; Greg O’Donnell; Ryan Otte; Laura Price; Larissa Rakhilina; Berengere Sauvagnat; Sharad Sharma; Sriram Tyagarajan; Hyun Woo; Daniel F. Wyss; Serena Xu; David Jonathan Be...; George H. Addona
• Keywords: Sting

Pharmacological activation of the STING (stimulator interferon genes)-controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report identification MSA-2, an orally available non-nucleotide human agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated stimulated interferon-β secretion in tumors, induced regression with durable antitumor immunity, synergized anti-PD-1 therapy. Experimental theoretical analyses showed that exists as interconverting monomers dimers solution, but only bind activate STING. This model was validated by using synthetic covalent dimers, which potent agonists. Cellular potency increased upon extracellular acidification, mimics microenvironment. These properties appear to underpin favorable activity tolerability profiles effective systemic administration MSA-2.