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      Discovery of BI 7446: A Potent Cyclic Dinucleotide STING Agonist with Broad-Spectrum Variant Activity for the Treatment of Cancer.

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          Abstract

          Activating the stimulator of interferon genes (STING) pathway with STING agonists is an attractive immune oncology concept to treat patients with tumors that are refractory to single-agent anti-PD-1 therapy. For best clinical translatability and broad application to cancer patients, STING agonists with potent cellular activation of all STING variants are desired. Novel cyclic dinucleotide (CDN)-based selective STING agonists were designed and synthesized comprising noncanonical nucleobase, ribose, and phosphorothioate moieties. This strategy led to the discovery of 2',3'-CDN 13 (BI 7446), which features unprecedented potency and activates all five STING variants in cellular assays. ADME profiling revealed that CDN 13 has attractive drug-like properties for development as an intratumoral agent. Injection of low doses of CDN 13 into tumors in mice induced long-lasting, tumor-specific immune-mediated tumor rejection. Based on its compelling preclinical profile, BI 7446 has been advanced to clinical trials (monotherapy and in combination with anti-PD-1 antibody).

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          Author and article information

          Journal
          J Med Chem
          Journal of medicinal chemistry
          American Chemical Society (ACS)
          1520-4804
          0022-2623
          Jul 27 2023
          : 66
          : 14
          Affiliations
          [1 ] Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany.
          [2 ] Boehringer Ingelheim RCV GmbH & Co KG, 1120 Vienna, Austria.
          Article
          10.1021/acs.jmedchem.3c00510
          37450324
          25bb726e-3997-49e7-8e9c-bd0fed5c11c8
          History

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