Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction

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 () and Qin Yan ()
Additional contact information
Mingzhu Yin: Central South University
Ying Guo: Central South University
Rui Hu: Central South University
Wesley L. Cai: Yale School of Medicine
Yao Li: Central South University
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
Xiang Chen: Central South University
Qin Yan: Yale School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/s41467-020-15290-0 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:11:y:2020:i:1:d:10.1038_s41467-020-15290-0

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

DOI: 10.1038/s41467-020-15290-0

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 ().