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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
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    Cited by:

    1. 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.
    2. 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.
    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.

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