Journal Article

Activation of human STING by a molecular glue-like compound

Nicholson, Thomas B., Wu, Hua, Feng, Yan, Miller, Howard R., Tria, George S., Pham, Helen T., Chen, Lihao, Michaud, Gregory A., Wang, Yuan, Yu, Gary, Broom, Wendy, Cho, Charles Y., Bai, Xiao-Chen, Hornak, Viktor, Mao, Xiaohong, Tutter, Antonin, Sivick, Kelsey E., Canham, Stephen M., Tallarico, John A., Brittain, Scott M., Schirle, Markus, Patel, Sejal J., Jenkins, Jeremy L., Digan, Mary Ellen, McWhirter, Sarah M., Zhang, Xuewu, Chen, Yu, McKenna, Jeffery M., Ross, Nathan T., Liu, Guoxun, Jain, Rishi K., Chen, Christine H., Zheng, Lianxing, Li, Jie, Henault, Martin

2024

Overview

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. A cell-based phenotypic screen led to the discovery of compounds called NVS-STGs, which bind to the N-terminal domain of STING and act as a molecular glue to induce higher-order oligomerization and activation.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 60 APPLIED LIFE SCIENCES / 631/154/1435/2163 / 631/250 / 631/535 / 631/67/1059 / 631/92/613 / Adapter proteins / Adaptor Proteins, Signal Transducing - metabolism / Animal models / Animals / Anticancer properties / Antitumor activity / Binding / Biochemical Engineering / Biochemistry / Biological Assay / Bioorganic Chemistry / cancer therapy / Cell Biology / Cell culture / Chemistry / Chemistry and Materials Science / Chemistry/Food Science / Cytosol / high-throughput screening / Humans / Immune response / Immune system / Immunity, Innate / immunology / Innate immunity / Ligands / Membrane Proteins - metabolism / Oligomerization / small molecules / Stimulators / structural biology / Transmembrane domains