2. Academic Validation
  3. Activation of human STING by a molecular glue-like compound

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

Affiliations

  • 1 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2 Novartis Institutes for BioMedical Research, Cambridge, MA, USA. steve.canham@novartis.com.
  • 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. xuewu.zhang@utsouthwestern.edu.
  • 7 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA. xuewu.zhang@utsouthwestern.edu.
  • 8 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA. xiaochen.bai@utsouthwestern.edu.
  • 9 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA. xiaochen.bai@utsouthwestern.edu.
  • 10 Novartis Institutes for BioMedical Research, Cambridge, MA, USA. yan.feng@novartis.com.
  • # 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157214
    99.76%, STING的分子胶
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