Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4,ACS Chemical Biology

当前位置： X-MOL 学术 › ACS Chem. Biol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2015-06-16 00:00:00 , DOI: 10.1021/acschembio.5b00216
Michael Zengerle ₁ , Kwok-Ho Chan ₁ , Alessio Ciulli ₁

Affiliation

The Bromo- and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation, epigenetics, and cancer and are the targets of pan-BET selective bromodomain inhibitor JQ1. However, the lack of intra-BET selectivity limits the scope of current inhibitors as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We designed Proteolysis Targeted Chimeras (PROTACs) that tether JQ1 to a ligand for the E3 ubiquitin ligase VHL, aimed at triggering the intracellular destruction of BET proteins. Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 over BRD2 and BRD3. The activity of MZ1 is dependent on binding to VHL but is achieved at a sufficiently low concentration not to induce stabilization of HIF-1α. Gene expression profiles of selected cancer-related genes responsive to JQ1 reveal distinct and more limited transcriptional responses induced by MZ1, consistent with selective suppression of BRD4. Our discovery opens up new opportunities to elucidate the cellular phenotypes and therapeutic implications associated with selective targeting of BRD4.

中文翻译：

BET Bromodomain 蛋白 BRD4 的选择性小分子降解

溴和末端 (BET) 蛋白 BRD2、BRD3 和 BRD4 在转录调控、表观遗传学和癌症中发挥重要作用，并且是泛 BET 选择性溴结构域抑制剂 JQ1 的靶标。然而，BET 内选择性的缺乏限制了当前抑制剂作为靶点验证探针的范围，并可能导致治疗环境中不需要的副作用或毒性。我们设计了蛋白水解靶向嵌合体 (PROTACs)，将 JQ1 连接到 E3 泛素连接酶 VHL 的配体上，旨在触发 BET 蛋白的细胞内破坏。与 BRD2 和 BRD3 相比，化合物 MZ1 有效且快速地诱导 BRD4 的可逆、持久和出人意料的选择性去除。MZ1 的活性依赖于与 VHL 的结合，但以足够低的浓度实现，不会诱导 HIF-1α 的稳定化。对 JQ1 有反应的选定癌症相关基因的基因表达谱揭示了由 MZ1 诱导的不同且更有限的转录反应，这与 BRD4 的选择性抑制一致。我们的发现为阐明与选择性靶向 BRD4 相关的细胞表型和治疗意义开辟了新的机会。

更新日期：2015-06-16

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南