机构：[1]Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, XiangyaHospital, Central South University, Changsha, Hunan 410008, China[2]Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA[3]School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China[4]Ningbo Wenda Pharma, Ninghai,Zhejiang 315622, China[5]Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, Hunan410078, China[6]Key Laboratory of Carcinogenesis of Ministry of Health, Cancer Research Institute, Central South University, Changsha, Hunan 410078,China[7]Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha 410011, China[8]Yale Cancer Center, Yale School ofMedicine, New Haven, CT 06520, USA[9]Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
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.
基金：
The research was
supported in part by Department of Defense Breast Cancer Research Program Award W81XWH-15-1-0117 (to Q. Yan), NCI P50CA121974 and R01CA237586 (to Q. Yan),
The Sokoloff Family-MRA Team Science Award (to Q. Yan), and Natural Science
Foundation of China General Program grant 81874138 (to M.Y.), 81728014 (to Y.T.),
and Major Projects of International Cooperation and Exchanges grant 81620108024
(to X.C.).
语种：
外文
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第一作者：
第一作者机构：[1]Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, XiangyaHospital, Central South University, Changsha, Hunan 410008, China[2]Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA
通讯作者：
通讯机构：[1]Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, XiangyaHospital, Central South University, Changsha, Hunan 410008, China[2]Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA[8]Yale Cancer Center, Yale School ofMedicine, New Haven, CT 06520, USA[9]Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
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