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Design of amidobenzimidazole STING receptor agonists with systemic activity

Author

Listed:
  • Joshi M. Ramanjulu

    (GlaxoSmithKline)

  • G. Scott Pesiridis

    (GlaxoSmithKline)

  • Jingsong Yang

    (GlaxoSmithKline)

  • Nestor Concha

    (GlaxoSmithKline)

  • Robert Singhaus

    (GlaxoSmithKline)

  • Shu-Yun Zhang

    (GlaxoSmithKline)

  • Jean-Luc Tran

    (GlaxoSmithKline)

  • Patrick Moore

    (GlaxoSmithKline)

  • Stephanie Lehmann

    (Cellzome, GlaxoSmithKline R&D)

  • H. Christian Eberl

    (Cellzome, GlaxoSmithKline R&D)

  • Marcel Muelbaier

    (Cellzome, GlaxoSmithKline R&D)

  • Jessica L. Schneck

    (GlaxoSmithKline)

  • Jim Clemens

    (GlaxoSmithKline)

  • Michael Adam

    (GlaxoSmithKline)

  • John Mehlmann

    (GlaxoSmithKline)

  • Joseph Romano

    (GlaxoSmithKline)

  • Angel Morales

    (GlaxoSmithKline)

  • James Kang

    (GlaxoSmithKline)

  • Lara Leister

    (GlaxoSmithKline)

  • Todd L. Graybill

    (GlaxoSmithKline)

  • Adam K. Charnley

    (GlaxoSmithKline)

  • Guosen Ye

    (GlaxoSmithKline)

  • Neysa Nevins

    (GlaxoSmithKline)

  • Kamelia Behnia

    (GlaxoSmithKline)

  • Amaya I. Wolf

    (GlaxoSmithKline)

  • Viera Kasparcova

    (GlaxoSmithKline)

  • Kelvin Nurse

    (GlaxoSmithKline)

  • Liping Wang

    (GlaxoSmithKline)

  • Ana C. Puhl

    (GlaxoSmithKline)

  • Yue Li

    (GlaxoSmithKline)

  • Michael Klein

    (GlaxoSmithKline)

  • Christopher B. Hopson

    (GlaxoSmithKline)

  • Jeffrey Guss

    (GlaxoSmithKline)

  • Marcus Bantscheff

    (Cellzome, GlaxoSmithKline R&D)

  • Giovanna Bergamini

    (Cellzome, GlaxoSmithKline R&D)

  • Michael A. Reilly

    (GlaxoSmithKline)

  • Yiqian Lian

    (GlaxoSmithKline)

  • Kevin J. Duffy

    (GlaxoSmithKline)

  • Jerry Adams

    (GlaxoSmithKline)

  • Kevin P. Foley

    (GlaxoSmithKline)

  • Peter J. Gough

    (GlaxoSmithKline)

  • Robert W. Marquis

    (GlaxoSmithKline)

  • James Smothers

    (GlaxoSmithKline)

  • Axel Hoos

    (GlaxoSmithKline)

  • John Bertin

    (GlaxoSmithKline)

Abstract

Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA1. The development of compounds that modulate STING has recently been the focus of intense research for the treatment of cancer and infectious diseases and as vaccine adjuvants2. To our knowledge, current efforts are focused on the development of modified cyclic dinucleotides that mimic the endogenous STING ligand cGAMP; these have progressed into clinical trials in patients with solid accessible tumours amenable to intratumoral delivery3. Here we report the discovery of a small molecule STING agonist that is not a cyclic dinucleotide and is systemically efficacious for treating tumours in mice. We developed a linking strategy to synergize the effect of two symmetry-related amidobenzimidazole (ABZI)-based compounds to create linked ABZIs (diABZIs) with enhanced binding to STING and cellular function. Intravenous administration of a diABZI STING agonist to immunocompetent mice with established syngeneic colon tumours elicited strong anti-tumour activity, with complete and lasting regression of tumours. Our findings represent a milestone in the rapidly growing field of immune-modifying cancer therapies.

Suggested Citation

  • Joshi M. Ramanjulu & G. Scott Pesiridis & Jingsong Yang & Nestor Concha & Robert Singhaus & Shu-Yun Zhang & Jean-Luc Tran & Patrick Moore & Stephanie Lehmann & H. Christian Eberl & Marcel Muelbaier & , 2018. "Design of amidobenzimidazole STING receptor agonists with systemic activity," Nature, Nature, vol. 564(7736), pages 439-443, December.
    • Handle: RePEc:nat:nature:v:564:y:2018:i:7736:d:10.1038_s41586-018-0705-y
    DOI: 10.1038/s41586-018-0705-y
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    Citations

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    Cited by:

    1. Xuan Wang & Yingqi Liu & Chencheng Xue & Yan Hu & Yuanyuan Zhao & Kaiyong Cai & Menghuan Li & Zhong Luo, 2022. "A protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    2. Qiwei Wang & Johann S. Bergholz & Liya Ding & Ziying Lin & Sheheryar K. Kabraji & Melissa E. Hughes & Xiadi He & Shaozhen Xie & Tao Jiang & Weihua Wang & Jason J. Zoeller & Hye-Jung Kim & Thomas M. Ro, 2022. "STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Dario Zimmerli & Chiara S. Brambillasca & Francien Talens & Jinhyuk Bhin & Renske Linstra & Lou Romanens & Arkajyoti Bhattacharya & Stacey E. P. Joosten & Ana Moises Silva & Nuno Padrao & Max D. Welle, 2022. "MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    4. Tomoko Yamamori Morita & Jie Yu & Yukie Kashima & Ryo Kamata & Gaku Yamamoto & Tatsunori Minamide & Chiaki Mashima & Miyuki Yoshiya & Yuta Sakae & Toyohiro Yamauchi & Yumi Hakozaki & Shun-ichiro Kagey, 2023. "CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    5. Peng Zhang & Aida Rashidi & Junfei Zhao & Caylee Silvers & Hanxiang Wang & Brandyn Castro & Abby Ellingwood & Yu Han & Aurora Lopez-Rosas & Markella Zannikou & Crismita Dmello & Rebecca Levine & Ting , 2023. "STING agonist-loaded, CD47/PD-L1-targeting nanoparticles potentiate antitumor immunity and radiotherapy for glioblastoma," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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