An orally available non-nucleotide STING agonist with antitumor activity.

Autor: Pan BS; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Perera SA; 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., Piesvaux JA; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Presland JP; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Schroeder GK; 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., Cumming JN; Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA., Trotter BW; 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., Altman MD; Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA., Buevich AV; Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA., Cash B; Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA., Cemerski S; Department of Discovery Oncology, Merck & Co., Inc., Kenilworth, NJ, USA., Chang W; Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA., Chen Y; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Dandliker PJ; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Feng G; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Haidle A; Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA., Henderson T; Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA., Jewell J; Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA., Kariv I; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Knemeyer I; Department of Pharmacokinetics, Merck & Co., Inc., Kenilworth, NJ, USA., Kopinja J; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Lacey BM; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Laskey J; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Lesburg CA; Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA., Liang R; Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA., Long BJ; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Lu M; Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA., Ma Y; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Minnihan EC; Department of Discovery Pharmaceutical Sciences, Merck & Co., Inc., Kenilworth, NJ, USA., O'Donnell G; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Otte R; Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA., Price L; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Rakhilina L; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Sauvagnat B; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Sharma S; Department of Discovery Oncology, Merck & Co., Inc., Kenilworth, NJ, USA., Tyagarajan S; Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA., Woo H; Department of Pharmacokinetics, Merck & Co., Inc., Kenilworth, NJ, USA., Wyss DF; Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA., Xu S; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA., Bennett DJ; 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., Addona GH; 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.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2020 Aug 21; Vol. 369 (6506).
DOI: 10.1126/science.aba6098
Abstrakt: 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.
(Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze: MEDLINE
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