By screening a large small-molecule library, Pan et al. identified an orally available small-molecule STING agonist (MSA-2), which bound to mouse and human STING as a noncovalent dimer and exhibited higher cellular potency in an acidified tumor microenvironment. Intratumoral, subcutaneous, and orally administered MSA-2 induced interferon-β production, tumor regression, and durable immunity against rechallenge in syngeneic MC38 tumor model. In mouse tumor models poorly responsive to anti-PD-1 therapy (MC38, CT26, B16F10, and LL-2), combination with MSA-2 enhanced tumor control and prolonged survival over monotherapy.
Contributed by Shishir Pant
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-_ 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.
Author Info: (1) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (2) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. samanthi_per
Author Info: (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 Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (4) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (5) 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. (6) Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. (7) 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. (8) Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. (9) Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. (10) Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. (11) Department of Discovery Oncology, Merck & Co., Inc., Kenilworth, NJ, USA. (12) Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. (13) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (14) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (15) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (16) Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. (17) Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. (18) Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. (19) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (20) Department of Pharmacokinetics, Merck & Co., Inc., Kenilworth, NJ, USA. (21) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (22) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (23) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (24) Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. (25) Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. (26) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (27) Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. (28) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (29) Department of Discovery Pharmaceutical Sciences, Merck & Co., Inc., Kenilworth, NJ, USA. (30) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (31) Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. (32) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (33) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (34) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (35) Department of Discovery Oncology, Merck & Co., Inc., Kenilworth, NJ, USA. (36) Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. (37) Department of Pharmacokinetics, Merck & Co., Inc., Kenilworth, NJ, USA. (38) Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA. (39) Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA. (40) 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. (41) 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.
