Nonselective inhibition of the epigenetic transcriptional regulator BET induces marked lymphoid and hematopoietic toxicity in mice
Nonselective inhibition of the epigenetic transcriptional regulator BET induces marked lymphoid and hematopoietic toxicity in mice
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DOI：
10.1016/j.taap.2016.03.013
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发表时间：
2016-06-01
影响因子：
3.8
通讯作者：
Danilenko, Dimitry M.
中科院分区：
文献类型：
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作者：
Lee, Dong U.;Katavolos, Paula;Danilenko, Dimitry M.
溴和额外末端（BET）蛋白（BRD 2、BRD 3、BRD 4和BRDT）是有效表达生长促进、细胞周期进程和抗凋亡基因所需的表观遗传转录调节因子。通过它们的布罗莫结构域，这些蛋白质与组蛋白的乙酰化赖氨酸残基结合，并被募集到转录活性染色质。BET-组蛋白相互作用的抑制提供了治疗可能具有表观遗传失调的疾病的易处理的治疗策略。JQ 1是一种小分子，可阻断BET与组蛋白的相互作用。已显示其在体外降低患者来源的多发性骨髓瘤的增殖，并在异种移植小鼠模型中降低体内肿瘤负荷。虽然靶向BET似乎是一种可行且有效的方法，但BET抑制的非临床安全性特征仍有待明确。我们报告说，在有效暴露下给予JQ 1的小鼠表现出淋巴和免疫细胞区室的剂量依赖性减少。在较高剂量下，JQ 1不耐受，并且由于诱导显著的体重减轻，导致提前安乐死。淋巴组织的流式细胞术分析显示，B淋巴细胞和T淋巴细胞均减少，同时外周白色血细胞减少，经血液学证实。对JQ 1的非活性对映异构体的进一步研究表明，这些体内作用是靶向介导的，并且由于化学结构而不是通过次级药理学引起的。(C)2016 Elsevier Inc. All rights reserved.
Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4 and BRDT) are epigenetic transcriptional regulators required for efficient expression of growth promoting, cell cycle progression and antiapoptotic genes. Through their bromodomain, these proteins bind to acetylated lysine residues of histones and are recruited to transcriptionally active chromatin. Inhibition of the BET-histone interaction provides a tractable therapeutic strategy to treat diseases that may have epigenetic dysregulation. JQ1 is a small molecule that blocks BET interaction with histones. It has been shown to decrease proliferation of patient-derived multiple myeloma in vitro and to decrease tumor burden in vivo in xenograft mouse models. While targeting BET appears to be a viable and efficacious approach, the nonclinical safety profile of BET inhibition remains to be well-defined. We report that mice dosed with JQ1 at efficacious exposures demonstrate dose-dependent decreases in their lymphoid and immune cell compartments. At higher doses, JQ1 was not tolerated and due to induction of significant body weight loss led to early euthanasia. Flow cytometry analysis of lymphoid tissues showed a decrease in both B- and T-lymphocytes with a concomitant decrease in peripheral white blood cells that was confirmed by hematology. Further investigation with the inactive enantiomer of JQ1 showed that these in vivo effects were on-target mediated and not elicited through secondary pharmacology due to chemical structure. (C) 2016 Elsevier Inc. All rights reserved.