2. Academic Validation
  3. Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction

Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction

  • Nat Commun. 2020 Apr 14;11(1):1833. doi: 10.1038/s41467-020-15290-0.
Mingzhu Yin 1 2,  Ying Guo 3,  Rui Hu 3,  Wesley L Cai 4,  Yao Li 3 4,  Shiyao Pei 3,  Hongyin Sun 3,  Cong Peng 3,  Jiali Li 4,  Rui Ye 4,  Qiaohong Yang 5,  Nenghui Wang 6,  Yongguang Tao 7 8 9,  Xiang Chen 10,  Qin Yan 11 12 13
Affiliations

Affiliations

  • 1 Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. [email protected].
  • 2 Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, USA. [email protected].
  • 3 Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
  • 4 Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, USA.
  • 5 School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
  • 6 Ningbo Wenda Pharma, Ninghai, Zhejiang, 315622, China.
  • 7 Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, Hunan, 410078, China.
  • 8 Key Laboratory of Carcinogenesis of Ministry of Health, Cancer Research Institute, Central South University, Changsha, Hunan, 410078, China.
  • 9 Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, China.
  • 10 Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. [email protected].
  • 11 Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, USA. [email protected].
  • 12 Yale Cancer Center, Yale School of Medicine, New Haven, CT, 06520, USA. [email protected].
  • 13 Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, 06520, USA. [email protected].
PMID: 32286255 DOI: 10.1038/s41467-020-15290-0
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.

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