2. Academic Validation
  3. An orally available non-nucleotide STING agonist with antitumor activity

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

Affiliations

  • 1 Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA.
  • 2 Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. samanthi_perera@merck.com gottfried.schroeder@merck.com wes.trotter@kronosbio.com jonathan.bennett@merck.com george_addona@merck.com.
  • 3 Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA.
  • 4 Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. samanthi_perera@merck.com gottfried.schroeder@merck.com wes.trotter@kronosbio.com jonathan.bennett@merck.com george_addona@merck.com.
  • 5 Department of Discovery Oncology, Merck & Co., Inc., Kenilworth, NJ, USA.
  • 6 Department of Pharmacokinetics, Merck & Co., Inc., Kenilworth, NJ, USA.
  • 7 Department of Discovery Pharmaceutical Sciences, Merck & Co., Inc., Kenilworth, NJ, USA.
  • # Contributed equally.
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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