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.
Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, USA.
Nat Commun. 2020 Apr 14;11(1):1833. doi: 10.1038/s41467-020-15290-0.
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.
小分子抑制剂的溴结构域和末端结构域（BET）家族蛋白是癌症治疗有前途的选择。然而，目前的 BET 抑制剂受到其效力或口服生物利用度的限制。在这里，我们报告了 NHWD-870 的发现和表征，这是一种 BET 抑制剂，比三种主要的临床阶段 BET 抑制剂 BMS-986158、OTX-015 和 GSK-525762 更有效。NHWD-870 导致肿瘤缩小或显著抑制 9 个异种移植或同基因模型中的肿瘤生长。除了下调 c-MYC 和直接抑制肿瘤细胞增殖的能力外，NHWD-870 通过多种机制阻断肿瘤相关巨噬细胞（TAMs）的增殖，部分通过降低肿瘤细胞表达和分泌巨噬细胞集落刺激因子 CSF1。NHWD-870 通过抑制 BRD4 及其靶标 HIF1α 来抑制 CSF1 的表达。总之，这些结果揭示了 BRD4 抑制抑制肿瘤生长的机制，并支持进一步开发 NHWD-870 来治疗实体瘤。
