Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer.
Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer.
复制标题
DOI：
10.1158/0008-5472.can-16-2622
复制
发表时间：
2017-05-01
期刊：
影响因子：
11.2
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Bai L;Zhou B;Yang CY;Ji J;McEachern D;Przybranowski S;Jiang H;Hu J;Xu F;Zhao Y;Liu L;Fernandez-Salas E;Xu J;Dou Y;Wen B;Sun D;Meagher J;Stuckey J;Hayes DF;Li S;Ellis MJ;Wang S
三阴性乳腺癌（TNBC）在临床上仍然具有挑战性，缺乏靶向治疗的选择。在这项研究中，我们报告了第二代BET溴结构域（BRD）抑制剂，BETd-246，它具有优越的上级选择性，效力和抗肿瘤活性的发展。在人TNBC细胞中，BETd-246在暴露1小时内以低纳摩尔浓度诱导BET转录因子降解，导致强烈的生长抑制和细胞凋亡。在TNBC细胞中，BETd-246比其亲本BET抑制剂化合物BETi-211更强效和有效。RNA-seq分析显示，与上调和下调类似数量的基因的BETi-211处理相比，在用BETd-246处理的细胞中，参与增殖和凋亡的大量基因的显著下调。功能研究确定了MCL 1基因作为这些BET降解剂的关键下游效应子，其与BCL-xL的小分子抑制剂协同触发细胞凋亡。在人乳腺癌的多个鼠异种移植模型中，BETd-246和进一步优化的类似物BETd-260有效地耗尽肿瘤中的BET蛋白，并且在良好耐受的给药方案下表现出强的抗肿瘤活性。总的来说，我们的研究结果显示了BET蛋白的特异性靶向降解如何产生TNBC治疗的有效治疗策略。
Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In this study, we report the development of a second-generation BET bromodomain (BRD) inhibitor, BETd-246, which exhibits superior selectivity, potency and antitumor activity. In human TNBC cells, BETd-246 induced degradation of BET transcription factors at low nanomolar concentrations within 1 hr of exposure, resulting in robust growth inhibition and apoptosis. BETd-246 was more potent and effective in TNBC cells than its parental BET inhibitor compound BETi-211. RNA-seq analysis revealed predominant downregulation of a large number of genes involved in proliferation and apoptosis in cells treated with BETd-246, as compared to BETi-211 treatment which upregulated and downregulated a similar number of genes. Functional investigations identified the MCL1 gene as a critical downstream effector of these BET degraders, which synergized with small molecule inhibitors of BCL-xL in triggering apoptosis. In multiple murine xenograft models of human breast cancer, BETd-246 and a further optimized analogue BETd-260 effectively depleted BET proteins in tumors and exhibited strong antitumor activities at well-tolerated dosing schedules. Overall, our findings show how specific targeting of BET proteins for degradation yields an effective therapeutic strategy for TNBC treatment.