The Discovery of I-BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor
The Discovery of I-BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor
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DOI：
10.1021/jm5010539
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发表时间：
2014-10-09
影响因子：
7.3
通讯作者：
Nicodeme, Edwige
中科院分区：
文献类型：
--
作者：
Gosmini, Romain;Van Loc Nguyen;Nicodeme, Edwige
含溴结构域蛋白的 BET 家族通过其作为组蛋白密码的表观遗传读取器的功能，调节多个与治疗相关的基因的表达，包括那些涉及肿瘤细胞生长和炎症的基因。 BET 溴结构域抑制剂具有深远的抗增殖和抗炎作用。转化为肿瘤学和炎症模型中的功效，首批化合物现已进入临床试验。 BET 令人兴奋的生物学特性引起了人们对新型抑制剂类别的发现的极大兴趣。在这里，我们描述了通过上调载脂蛋白 A1 鉴定新型四氢喹啉系列，并优化为在败血性休克和神经母细胞瘤小鼠模型中具有活性的有效化合物。在分子水平上，这些效应是通过抑制 BET 溴结构域而产生的。X 射线晶体学揭示了相互作用，解释了结合的结构-活性关系。由此产生的先导分子 I-BET726 代表了一类新型、有效、选择性的基于四氢喹啉的 BET 抑制剂。
Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which. translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apoliproprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibiton of BET bromodomains X-rays crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.