posted on 2022-02-02, 21:44authored byEmily C. Cherney, Liping Zhang, Julian Lo, Tram Huynh, Donna Wei, Vijay Ahuja, Claude Quesnelle, Gary L. Schieven, Alan Futran, Gregory A. Locke, Zeyu Lin, Laura Monereau, Charu Chaudhry, Jordan Blum, Sha Li, Mark Fereshteh, Bifang Li-Wang, Sanjeev Gangwar, Chin Pan, Colin Chong, Xiao Zhu, Shana L. Posy, John S. Sack, Ping Zhang, Max Ruzanov, Mary Harner, Fahad Akhtar, Gretchen M. Schroeder, Gregory Vite, Brian Fink
The
identification of agonists of the stimulator of interferon
genes (STING) pathway has been an area of intense research due to
their potential to enhance innate immune response and tumor immunogenicity
in the context of immuno-oncology therapy. Initial efforts to identify
STING agonists focused on the modification of 2′,3′-cGAMP
(1) (an endogenous STING activator ligand) and other
closely related cyclic dinucleotides (CDNs). While these efforts have
successfully identified novel CDNs that have progressed into the clinic,
their utility is currently limited to patients with solid tumors that
STING agonists can be delivered to intratumorally. Herein, we report
the discovery of a unique class of non-nucleotide small-molecule STING
agonists that demonstrate antitumor activity when dosed intratumorally
in a syngeneic mouse model.