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

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).