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
  • 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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