Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-04-14

AUTHORS

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

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. More... »

PAGES

1833

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-020-15290-0

    DOI

    http://dx.doi.org/10.1038/s41467-020-15290-0

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1126646693

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/32286255


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