Discovery of Non-Nucleotide Small-Molecule STING Agonists <i>via</i> Chemotype Hybridization
Emily C. Cherney, Liping Zhang, Julian B. Lo, Tram Huynh, Donna Wei, Vijay T. Ahuja, Claude Quesnelle, Gary L. Schieven, Alan Futran, Gregory 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 Posy, John S. Sack, Ping Zhang, Max Ruzanov, Mary J. Harner, Fahad Akhtar, Gretchen M. Schroeder, Gregory D. Vite, Brian E. Fink
Abstract
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.