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

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.

Nature Chemical Biology

Activation of human STING by a molecular glue-like compound

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

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 was 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 the authors report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING.The authors' 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 mol. glue.The authors' functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models.

100 项与 NVS-STG2 相关的药物交易

登录后查看更多信息