SPA70 is a potent antagonist of human pregnane X receptor

Wenwei Lin, Yue-Ming Wang, Sergio C. Chai, Lili Lv, Jie Zheng, Jing Wu, Qijun Zhang, Yong-Dong Wang, Patrick R. Griffin and Taosheng Chen ()
Additional contact information
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

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-017-00780-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00780-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-017-00780-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().