An orally available non-nucleotide STING agonist with antitumor activity
(1) Pan BS (2) Perera SA (3) Piesvaux JA (4) Presland JP (5) Schroeder GK (6) Cumming JN (7) Trotter BW (8) Altman MD (9) Buevich AV (10) Cash B (11) Cemerski S (12) Chang W (13) Chen Y (14) Dandliker PJ (15) Feng G (16) Haidle A (17) Henderson T (18) Jewell J (19) Kariv I (20) Knemeyer I (21) Kopinja J (22) Lacey BM (23) Laskey J (24) Lesburg CA (25) Liang R (26) Long BJ (27) Lu M (28) Ma Y (29) Minnihan EC (30) O'Donnell G (31) Otte R (32) Price L (33) Rakhilina L (34) Sauvagnat B (35) Sharma S (36) Tyagarajan S (37) Woo H (38) Wyss DF (39) Xu S (40) Bennett DJ (41) Addona GH
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
(1) Pan BS (2) Perera SA (3) Piesvaux JA (4) Presland JP (5) Schroeder GK (6) Cumming JN (7) Trotter BW (8) Altman MD (9) Buevich AV (10) Cash B (11) Cemerski S (12) Chang W (13) Chen Y (14) Dandliker PJ (15) Feng G (16) Haidle A (17) Henderson T (18) Jewell J (19) Kariv I (20) Knemeyer I (21) Kopinja J (22) Lacey BM (23) Laskey J (24) Lesburg CA (25) Liang R (26) Long BJ (27) Lu M (28) Ma Y (29) Minnihan EC (30) O'Donnell G (31) Otte R (32) Price L (33) Rakhilina L (34) Sauvagnat B (35) Sharma S (36) Tyagarajan S (37) Woo H (38) Wyss DF (39) Xu S (40) Bennett DJ (41) Addona GH
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
era@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.
