Activation of human STING by a molecular glue-like compound

  • Nat Chem Biol. 2023 Oct 12. doi: 10.1038/s41589-023-01434-y.
Jie Li  #  1 ,  Stephen M Canham  #  2 ,  Hua Wu  3 ,  Martin Henault  3 ,  Lihao Chen  3 ,  Guoxun Liu  4 ,  Yu Chen  4 ,  Gary Yu  3 ,  Howard R Miller  3 ,  Viktor Hornak  3 ,  Scott M Brittain  3 ,  Gregory A Michaud  3 ,  Antonin Tutter  3 ,  Wendy Broom  3 ,  Mary Ellen Digan  3 ,  Sarah M McWhirter  5 ,  Kelsey E Sivick  5 ,  Helen T Pham  3 ,  Christine H Chen  3 ,  George S Tria  3 ,  Jeffery M McKenna  3 ,  Markus Schirle  3 ,  Xiaohong Mao  3 ,  Thomas B Nicholson  3 ,  Yuan Wang  3 ,  Jeremy L Jenkins  3 ,  Rishi K Jain  3 ,  John A Tallarico  3 ,  Sejal J Patel  3 ,  Lianxing Zheng  3 ,  Nathan T Ross  3 ,  Charles Y Cho  4 ,  Xuewu Zhang  6  7 ,  Xiao-Chen Bai  8  9 ,  Yan Feng  10
Affiliations
  • 1. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2. Novartis Institutes for BioMedical Research, Cambridge, MA, USA. [email protected].
  • 3. Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
  • 4. Novartis Institutes for BioMedical Research, San Diego, CA, USA.
  • 5. Aduro Biotech, Inc., Berkeley, CA, USA.
  • 6. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 7. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 8. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 9. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 10. Novartis Institutes for BioMedical Research, Cambridge, MA, USA. [email protected].
  • # Contributed equally.
PMID: 37828400 DOI: 10.1038/s41589-023-01434-y
Abstract

Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to Infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING. Our cryo-EM structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models.

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