Activation of human STING by a molecular glue-like compound

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

doi:10.1038/s41589-023-01434-y

Activation of human STING by a molecular glue-like compound

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

Research output: Contribution to journal › Article › peer-review

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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. (Figure presented.)

Original language	English (US)
Pages (from-to)	365-372
Number of pages	8
Journal	Nature chemical biology
Volume	20
Issue number	3
DOIs	https://doi.org/10.1038/s41589-023-01434-y
State	Published - Mar 2024

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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Li, J., Canham, S. M., Wu, H., Henault, M., Chen, L., Liu, G., Chen, Y., Yu, G., Miller, H. R., Hornak, V., Brittain, S. M., Michaud, G. A., Tutter, A., Broom, W., Digan, M. E., McWhirter, S. M., Sivick, K. E., Pham, H. T., Chen, C. H., ... Feng, Y. (2024). Activation of human STING by a molecular glue-like compound. Nature chemical biology, 20(3), 365-372. https://doi.org/10.1038/s41589-023-01434-y

Li, J, Canham, SM, Wu, H, Henault, M, Chen, L, Liu, G, Chen, Y, Yu, G, Miller, HR, Hornak, V, Brittain, SM, Michaud, GA, Tutter, A, Broom, W, Digan, ME, McWhirter, SM, Sivick, KE, Pham, HT, Chen, CH, Tria, GS, McKenna, JM, Schirle, M, Mao, X, Nicholson, TB, Wang, Y, Jenkins, JL, Jain, RK, Tallarico, JA, Patel, SJ, Zheng, L, Ross, NT, Cho, CY, Zhang, X , Bai, XC & Feng, Y 2024, 'Activation of human STING by a molecular glue-like compound', Nature chemical biology, vol. 20, no. 3, pp. 365-372. https://doi.org/10.1038/s41589-023-01434-y

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title = "Activation of human STING by a molecular glue-like compound",

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. (Figure presented.)",

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

note = "Publisher Copyright: {\textcopyright} The Author(s) 2023.",

year = "2024",

month = mar,

doi = "10.1038/s41589-023-01434-y",

language = "English (US)",

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AU - Canham, Stephen M.

AU - Wu, Hua

AU - Henault, Martin

AU - Chen, Lihao

AU - Liu, Guoxun

AU - Chen, Yu

AU - Yu, Gary

AU - Miller, Howard R.

AU - Hornak, Viktor

AU - Brittain, Scott M.

AU - Michaud, Gregory A.

AU - Tutter, Antonin

AU - Broom, Wendy

AU - Digan, Mary Ellen

AU - McWhirter, Sarah M.

AU - Sivick, Kelsey E.

AU - Pham, Helen T.

AU - Chen, Christine H.

AU - Tria, George S.

AU - McKenna, Jeffery M.

AU - Schirle, Markus

AU - Mao, Xiaohong

AU - Nicholson, Thomas B.

AU - Wang, Yuan

AU - Jenkins, Jeremy L.

AU - Jain, Rishi K.

AU - Tallarico, John A.

AU - Patel, Sejal J.

AU - Zheng, Lianxing

AU - Ross, Nathan T.

AU - Cho, Charles Y.

AU - Zhang, Xuewu

AU - Bai, Xiao Chen

AU - Feng, Yan

PY - 2024/3

Y1 - 2024/3

N2 - 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. (Figure presented.)

AB - 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. (Figure presented.)

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JF - Nature chemical biology

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Activation of human STING by a molecular glue-like compound

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