An orally available non-nucleotide STING agonist with antitumor activity

  • Science. 2020 Aug 21;369(6506):eaba6098. doi: 10.1126/science.aba6098.
Bo-Sheng Pan   #  1 ,  Samanthi A Perera   #  2 ,  Jennifer A Piesvaux   #  1 ,  Jeremy P Presland   #  1 ,  Gottfried K Schroeder   #  2 ,  Jared N Cumming   #  3 ,  B Wesley Trotter   #  4 ,  Michael D Altman  3 ,  Alexei V Buevich  3 ,  Brandon Cash  3 ,  Saso Cemerski  5 ,  Wonsuk Chang  3 ,  Yiping Chen  1 ,  Peter J Dandliker  1 ,  Guo Feng  1 ,  Andrew Haidle  3 ,  Timothy Henderson  3 ,  James Jewell  3 ,  Ilona Kariv  1 ,  Ian Knemeyer  6 ,  Johnny Kopinja  1 ,  Brian M Lacey  1 ,  Jason Laskey  1 ,  Charles A Lesburg  3 ,  Rui Liang  3 ,  Brian J Long  1 ,  Min Lu  3 ,  Yanhong Ma  1 ,  Ellen C Minnihan  7 ,  Greg O'Donnell  1 ,  Ryan Otte  3 ,  Laura Price  1 ,  Larissa Rakhilina  1 ,  Berengere Sauvagnat  1 ,  Sharad Sharma  5 ,  Sriram Tyagarajan  3 ,  Hyun Woo  6 ,  Daniel F Wyss  3 ,  Serena Xu  1 ,  David Jonathan Bennett  4 ,  George H Addona  2
Affiliations
PMID: 32820094 DOI: 10.1126/science.aba6098
Abstract

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

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