Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 14, 2020
- Source ID
- 10.1038/s41467-020-15290-0
Entities
People
- Cong Peng
- Hongyin Sun
- Jiali Li
- Mingzhu Yin
- Nenghui Wang
- Qiaohong Yang
- Qin Yan
- Rui Hu
- Rui Ye
- Shiyao Pei
- Wesley L. Cai
- Xiang Chen
- Yao Li
- Ying Guo
- Yongguang Tao
Organizations
- Congressionally Directed Medical Research Programs
- Melanoma Research Alliance
- National Cancer Institute
- National Natural Science Foundation of China
- United States Department of Health and Human Services