| Autor: |
Kuttruff CA; Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany., Fleck M; Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany., Carotta S; Boehringer Ingelheim RCV GmbH & Co KG, 1120 Vienna, Austria., Arnhof H; Boehringer Ingelheim RCV GmbH & Co KG, 1120 Vienna, Austria., Bretschneider T; Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany., Dahmann G; Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany., Gremel G; Boehringer Ingelheim RCV GmbH & Co KG, 1120 Vienna, Austria., Grube A; Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany., Handschuh S; Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany., Heimann A; Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany., Hofmann MH; Boehringer Ingelheim RCV GmbH & Co KG, 1120 Vienna, Austria., Impagnatiello MA; Boehringer Ingelheim RCV GmbH & Co KG, 1120 Vienna, Austria., Nar H; Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany., Rast G; Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany., Schaaf O; Boehringer Ingelheim RCV GmbH & Co KG, 1120 Vienna, Austria., Schmidt E; Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany., Oost T; Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany. |
| Abstrakt: |
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). |
