Wang Shumei, Lei Kang, Lai Hsien-Tsung, Liu Tingting, Du Lupei, Wu Shwu-Yuan, Ye Xiaohan, Chiang Cheng-Ming, Li Minyong
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong 252059, China.
ACS Pharmacol Transl Sci. 2024 Mar 12;7(4):1178-1190. doi: 10.1021/acsptsci.4c00057. eCollection 2024 Apr 12.
A promising alternative for cancer treatment involves targeted inhibition of the epigenetic regulator bromodomain-containing protein 4 (BRD4); however, available BRD4 inhibitors are constrained by their potency, oral bioavailability, and cytotoxicity. Herein, to overcome the drawback of the translational BRD4 inhibitors, we describe a novel BRD4-p53 inhibitor, SDU-071, which suppresses BRD4 interaction with the p53 tumor suppressor and its biological activity in MDA-MB-231 triple-negative breast cancer (TNBC) cells in vitro and in vivo. This novel small-molecule BRD4-p53 inhibitor suppresses cell proliferation, migration, and invasion by downregulating the expression of BRD4-targeted genes, such as c-Myc and Mucin 5AC, and inducing cell cycle arrest and apoptosis, as demonstrated in cultured MDA-MB-231 TNBC cells. Its antitumor activity is illustrated in an orthotopic mouse xenograft mammary tumor model. Overall, our results show that SDU-071 is a viable option for potentially treating TNBC as a new BRD4-p53 inhibitor.
一种很有前景的癌症治疗替代方法是靶向抑制表观遗传调节因子含溴结构域蛋白4（BRD4）；然而，现有的BRD4抑制剂受到其效力、口服生物利用度和细胞毒性的限制。在此，为了克服转化型BRD4抑制剂的缺点，我们描述了一种新型的BRD4-p53抑制剂SDU-071，它在体外和体内均可抑制BRD4与p53肿瘤抑制因子的相互作用及其在MDA-MB-231三阴性乳腺癌（TNBC）细胞中的生物学活性。这种新型小分子BRD4-p53抑制剂通过下调BRD4靶向基因（如c-Myc和粘蛋白5AC）的表达来抑制细胞增殖、迁移和侵袭，并诱导细胞周期停滞和凋亡，如在培养的MDA-MB-231 TNBC细胞中所示。其抗肿瘤活性在原位小鼠异种移植乳腺肿瘤模型中得到了证实。总体而言，我们的结果表明，作为一种新型的BRD4-p53抑制剂，SDU-071是潜在治疗TNBC的可行选择。
