IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v11y2020i1d10.1038_s41467-020-15290-0.html
   My bibliography  Save this article

Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction

Author

Listed:
  • Mingzhu Yin

    (Central South University
    Yale School of Medicine)

  • Ying Guo

    (Central South University)

  • Rui Hu

    (Central South University)

  • Wesley L. Cai

    (Yale School of Medicine)

  • Yao Li

    (Central South University
    Yale School of Medicine)

  • Shiyao Pei

    (Central South University)

  • Hongyin Sun

    (Central South University)

  • Cong Peng

    (Central South University)

  • Jiali Li

    (Yale School of Medicine)

  • Rui Ye

    (Yale School of Medicine)

  • Qiaohong Yang

    (Guangzhou University of Chinese Medicine)

  • Nenghui Wang

    (Ningbo Wenda Pharma, Ninghai)

  • Yongguang Tao

    (Central South University
    Central South University
    Central South University)

  • Xiang Chen

    (Central South University)

  • Qin Yan

    (Yale School of Medicine
    Yale School of Medicine
    Yale School of Medicine)

Abstract

Small molecule inhibitor of the bromodomain and extraterminal domain (BET) family proteins is a promising option for cancer treatment. However, current BET inhibitors are limited by their potency or oral bioavailability. Here we report the discovery and characterization of NHWD-870, a BET inhibitor that is more potent than three major clinical stage BET inhibitors BMS-986158, OTX-015, and GSK-525762. NHWD-870 causes tumor shrinkage or significantly suppresses tumor growth in nine xenograft or syngeneic models. In addition to its ability to downregulate c-MYC and directly inhibit tumor cell proliferation, NHWD-870 blocks the proliferation of tumor associated macrophages (TAMs) through multiple mechanisms, partly by reducing the expression and secretion of macrophage colony-stimulating factor CSF1 by tumor cells. NHWD-870 inhibits CSF1 expression through suppressing BRD4 and its target HIF1α. Taken together, these results reveal a mechanism by which BRD4 inhibition suppresses tumor growth, and support further development of NHWD-870 to treat solid tumors.

Suggested Citation

  • Mingzhu Yin & Ying Guo & Rui Hu & Wesley L. Cai & Yao Li & Shiyao Pei & Hongyin Sun & Cong Peng & Jiali Li & Rui Ye & Qiaohong Yang & Nenghui Wang & Yongguang Tao & Xiang Chen & Qin Yan, 2020. "Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15290-0
    DOI: 10.1038/s41467-020-15290-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-020-15290-0
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-020-15290-0?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. Chunhong Yu & Xiaoyun Lei & Fang Chen & Song Mao & Lu Lv & Honglu Liu & Xueying Hu & Runhan Wang & Licong Shen & Na Zhang & Yang Meng & Yunfan Shen & Jiale Chen & Pishun Li & Shi Huang & Changwei Lin , 2022. "ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Michael R. Kelly & Kamila Wisniewska & Matthew J. Regner & Michael W. Lewis & Andrea A. Perreault & Eric S. Davis & Douglas H. Phanstiel & Joel S. Parker & Hector L. Franco, 2022. "A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    3. Anja Deutzmann & Delaney K. Sullivan & Renumathy Dhanasekaran & Wei Li & Xinyu Chen & Ling Tong & Wadie D. Mahauad-Fernandez & John Bell & Adriane Mosley & Angela N. Koehler & Yulin Li & Dean W. Felsh, 2024. "Nuclear to cytoplasmic transport is a druggable dependency in MYC-driven hepatocellular carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-13, 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:11:y:2020:i:1:d:10.1038_s41467-020-15290-0. 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.