An orally available non-nucleotide STING agonist with antitumor activity
- Science. 2020 Aug 21;369(6506):eaba6098. doi: 10.1126/science.aba6098.
- 1. Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA.
- 2. Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. [email protected] [email protected] [email protected] [email protected] [email protected].
- 3. Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA.
- 4. Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. [email protected] [email protected] [email protected] [email protected] [email protected].
- 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.
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.