IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v5y2014i1d10.1038_ncomms5935.html
   My bibliography  Save this article

Small-molecule Bax agonists for cancer therapy

Author

Listed:
  • Meiguo Xin

    (University of Florida
    Present address: Xemabio LLC, 4445 SW 35th Terrace Suite B, Gainesville SW Industrial Park, Gainesville, Florida 32608, USA.)

  • Rui Li

    (Emory University School of Medicine and Winship Cancer Institute of Emory University)

  • Maohua Xie

    (Emory University School of Medicine and Winship Cancer Institute of Emory University)

  • Dongkyoo Park

    (Emory University School of Medicine and Winship Cancer Institute of Emory University)

  • Taofeek K. Owonikoko

    (Emory University School of Medicine and Winship Cancer Institute of Emory University)

  • Gabriel L. Sica

    (Emory University School of Medicine and Winship Cancer Institute of Emory University)

  • Patrick E. Corsino

    (University of Florida)

  • Jia Zhou

    (Chemical Biology Program, University of Texas Medical Branch)

  • Chunyong Ding

    (Chemical Biology Program, University of Texas Medical Branch)

  • Mark A. White

    (Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch)

  • Andrew T. Magis

    (Institute for Systems Biology)

  • Suresh S. Ramalingam

    (Emory University School of Medicine and Winship Cancer Institute of Emory University)

  • Walter J. Curran

    (Emory University School of Medicine and Winship Cancer Institute of Emory University)

  • Fadlo R. Khuri

    (Emory University School of Medicine and Winship Cancer Institute of Emory University)

  • Xingming Deng

    (University of Florida
    Emory University School of Medicine and Winship Cancer Institute of Emory University)

Abstract

Bax, a central death regulator, is required at the decisional stage of apoptosis. We recently identified serine 184 (S184) of Bax as a critical functional switch controlling its proapoptotic activity. Here we used the structural pocket around S184 as a docking site to screen the NCI library of small molecules using the UCSF-DOCK programme suite. Three compounds, small-molecule Bax agonists SMBA1, SMBA2 and SMBA3, induce conformational changes in Bax by blocking S184 phosphorylation, facilitating Bax insertion into mitochondrial membranes and forming Bax oligomers. The latter leads to cytochrome c release and apoptosis in human lung cancer cells, which occurs in a Bax- but not Bak-dependent fashion. SMBA1 potently suppresses lung tumour growth via apoptosis by selectively activating Bax in vivo without significant normal tissue toxicity. Development of Bax agonists as a new class of anticancer drugs offers a strategy for the treatment of lung cancer and other Bax-expressing malignancies.

Suggested Citation

  • Meiguo Xin & Rui Li & Maohua Xie & Dongkyoo Park & Taofeek K. Owonikoko & Gabriel L. Sica & Patrick E. Corsino & Jia Zhou & Chunyong Ding & Mark A. White & Andrew T. Magis & Suresh S. Ramalingam & Wal, 2014. "Small-molecule Bax agonists for cancer therapy," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5935
    DOI: 10.1038/ncomms5935
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms5935
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms5935?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Andrea Lopez & Denis E. Reyna & Nadege Gitego & Felix Kopp & Hua Zhou & Miguel A. Miranda-Roman & Lars Ulrik Nordstrøm & Swathi-Rao Narayanagari & Ping Chi & Eduardo Vilar & Aristotelis Tsirigos & Evr, 2022. "Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5935. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.