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

  • J Med Chem. 2023 Jul 27;66(14):9376-9400. doi: 10.1021/acs.jmedchem.3c00510.
Christian A Kuttruff  1 ,  Martin Fleck  1 ,  Sebastian Carotta  2 ,  Heribert Arnhof  2 ,  Tom Bretschneider  1 ,  Georg Dahmann  1 ,  Gabriela Gremel  2 ,  Achim Grube  1 ,  Sandra Handschuh  1 ,  Annekatrin Heimann  1 ,  Marco H Hofmann  2 ,  Maria A Impagnatiello  2 ,  Herbert Nar  1 ,  Georg Rast  1 ,  Otmar Schaaf  2 ,  Esther Schmidt  1 ,  Thorsten Oost  1
Affiliations
  • 1. Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany.
  • 2. Boehringer Ingelheim RCV GmbH & Co KG, 1120 Vienna, Austria.
PMID: 37450324 DOI: 10.1021/acs.jmedchem.3c00510
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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