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SPA70 is a potent antagonist of human pregnane X receptor

Author

Listed:
  • Wenwei Lin

    (St. Jude Children’s Research Hospital)

  • Yue-Ming Wang

    (St. Jude Children’s Research Hospital)

  • Sergio C. Chai

    (St. Jude Children’s Research Hospital)

  • Lili Lv

    (Shanghai Medicilon Inc.)

  • Jie Zheng

    (The Scripps Research Institute)

  • Jing Wu

    (St. Jude Children’s Research Hospital)

  • Qijun Zhang

    (Shanghai Medicilon Inc.)

  • Yong-Dong Wang

    (St. Jude Children’s Research Hospital)

  • Patrick R. Griffin

    (The Scripps Research Institute)

  • Taosheng Chen

    (St. Jude Children’s Research Hospital)

Abstract

Many drugs bind to and activate human pregnane X receptor (hPXR) to upregulate drug-metabolizing enzymes, resulting in decreased drug efficacy and increased resistance. This suggests that hPXR antagonists have therapeutic value. Here we report that SPA70 is a potent and selective hPXR antagonist. SPA70 inhibits hPXR in human hepatocytes and humanized mouse models and enhances the chemosensitivity of cancer cells, consistent with the role of hPXR in drug resistance. Unexpectedly, SJB7, a close analog of SPA70, is an hPXR agonist. X-ray crystallography reveals that SJB7 resides in the ligand-binding domain (LBD) of hPXR, interacting with the AF-2 helix to stabilize the LBD for coactivator binding. Differential hydrogen/deuterium exchange analysis demonstrates that SPA70 and SJB7 interact with the hPXR LBD. Docking studies suggest that the lack of the para-methoxy group in SPA70 compromises its interaction with the AF-2, thus explaining its antagonism. SPA70 is an hPXR antagonist and promising therapeutic tool.

Suggested Citation

  • Wenwei Lin & Yue-Ming Wang & Sergio C. Chai & Lili Lv & Jie Zheng & Jing Wu & Qijun Zhang & Yong-Dong Wang & Patrick R. Griffin & Taosheng Chen, 2017. "SPA70 is a potent antagonist of human pregnane X receptor," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00780-5
    DOI: 10.1038/s41467-017-00780-5
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    Cited by:

    1. Efren Garcia-Maldonado & Andrew D. Huber & Sergio C. Chai & Stanley Nithianantham & Yongtao Li & Jing Wu & Shyaron Poudel & Darcie J. Miller & Jayaraman Seetharaman & Taosheng Chen, 2024. "Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Shengjie Fan & Yingxuan Yan & Ying Xia & Zhenyu Zhou & Lingling Luo & Mengnan Zhu & Yongli Han & Deqiang Yao & Lijun Zhang & Minglv Fang & Lina Peng & Jing Yu & Ying Liu & Xiaoyan Gao & Huida Guan & H, 2023. "Pregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions," Nature Communications, Nature, vol. 14(1), pages 1-23, December.

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