Details

Autor(en) / Beteiligte

• Kuttruff, Christian A.
• Fleck, Martin
• Carotta, Sebastian
• Arnhof, Heribert
• Bretschneider, Tom
• Dahmann, Georg
• Gremel, Gabriela
• Grube, Achim
• Handschuh, Sandra
• Heimann, Annekatrin
• Hofmann, Marco H.
• Impagnatiello, Maria A.
• Nar, Herbert
• Rast, Georg
• Schaaf, Otmar
• Schmidt, Esther
• Oost, Thorsten

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2023-07, Vol.66 (14), p.9376-9400

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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).