2. Academic Validation
  3. Discovery of Non-Nucleotide Small-Molecule STING Agonists via Chemotype Hybridization

Discovery of Non-Nucleotide Small-Molecule STING Agonists via Chemotype Hybridization

  • J Med Chem. 2022 Feb 24;65(4):3518-3538. doi: 10.1021/acs.jmedchem.1c01986.
Emily C Cherney 1,  Liping Zhang 1,  Julian Lo 1,  Tram Huynh 1,  Donna Wei 1,  Vijay Ahuja 1,  Claude Quesnelle 1,  Gary L Schieven 1,  Alan Futran 1,  Gregory A Locke 1,  Zeyu Lin 1,  Laura Monereau 1,  Charu Chaudhry 1,  Jordan Blum 1,  Sha Li 1,  Mark Fereshteh 1,  Bifang Li-Wang 1,  Sanjeev Gangwar 2,  Chin Pan 2,  Colin Chong 2,  Xiao Zhu 1,  Shana L Posy 1,  John S Sack 1,  Ping Zhang 1,  Max Ruzanov 1,  Mary Harner 1,  Fahad Akhtar 1,  Gretchen M Schroeder 1,  Gregory Vite 1,  Brian Fink 1
Affiliations

Affiliations

  • 1 Bristol Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • 2 Bristol Myers Squibb Research and Development, 700 Bay Rd, Redwood City, California 94063, United States.
PMID: 35108011 DOI: 10.1021/acs.jmedchem.1c01986
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.

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