Clinical trials for BET inhibitors run ahead of the science.
Clinical trials for BET inhibitors run ahead of the science.
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DOI：
10.1016/j.ddtec.2016.06.004
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Denis, Gerald V
中科院分区：
文献类型：
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作者：
Andrieu, Guillaume;Belkina, Anna C;Denis, Gerald V
BET 溴结构域蛋白小分子抑制剂的多项癌症临床试验已经启动。人们对抑制 BRD4 的抗增殖作用充满热情，BRD4 是这些抑制剂的靶点之一，被认为可以与 MYC 合作，而 MYC 是癌症治疗的长期期望的靶点。然而，目前三种体细胞BET蛋白（包括BRD2和BRD3）中没有对BRD4具有选择性的抑制剂。它们各自的功能部分重叠，并且与 BRD4 没有功能冗余。每个 BET 蛋白都控制着不同的转录途径，这些途径对于癌细胞增殖以外的功能非常重要，包括胰岛素产生、细胞因子基因转录、T 细胞分化、脂肪生成，以及最严重的是，主动抑制危险的潜伏病毒（如 HIV）。 BET 抑制剂已被证明可以重新激活人体细胞中的 HIV。未能认识到在所使用的浓度下，没有可用的 BET 抑制剂具有成员选择性，或者在进行这些临床试验之前未能建立良好的生物学基础来了解 BET 蛋白的多种功能，这是鲁莽的，可能会导致不良事件。来自新基础科学研究的更多机制信息应该能够正确关注最相关的癌症并定义预期的副作用概况。
Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated. There is enthusiasm for the anti-proliferative effect of inhibiting BRD4, one of the targets of these inhibitors, which is thought to cooperate with MYC, a long-desired target for cancer therapeutics. However, no current inhibitor is selective for BRD4 among the three somatic BET proteins, which include BRD2 and BRD3; their respective functions are partially overlapping and none are functionally redundant with BRD4. Each BET protein controls distinct transcriptional pathways that are important for functions beyond cancer cell proliferation, including insulin production, cytokine gene transcription, T cell differentiation, adipogenesis and most seriously, active repression of dangerous latent viruses like HIV. BET inhibitors have been shown to reactivate HIV in human cells. Failure to appreciate that at concentrations used, no available BET inhibitor is member-selective, or to develop a sound biological basis to understand the diverse functions of BET proteins before undertaking for these clinical trials is reckless and likely to lead to adverse events. More mechanistic information from new basic science studies should enable proper focus on the most relevant cancers and define the expected side effect profiles.