Inhibition of bromodomain-containing protein 9 for the prevention of epigenetically-defined drug resistance
Inhibition of bromodomain-containing protein 9 for the prevention of epigenetically-defined drug resistance
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DOI：
10.1016/j.bmcl.2017.05.063
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发表时间：
2017-08-01
影响因子：
2.7
通讯作者：
Stokoe, David
中科院分区：
文献类型：
--
作者：
Crawford, Terry D.;Vartanian, Steffan;Stokoe, David
含溴结构域蛋白9（BRD 9），一种后修饰组蛋白上乙酰化赖氨酸的表观遗传“阅读器”，在多种癌细胞系中上调。为了评估BRD 9在癌细胞系中的功能作用，我们鉴定了BRD 9布罗莫结构域的小分子抑制剂。从吡咯并吡啶酮先导化合物开始，我们使用基于结构的药物设计来鉴定有效且高选择性的体外工具化合物11（GNE-375）。虽然该化合物在细胞活力或基因表达测定中显示出最小的作用，但其在防止用EGFR抑制剂处理的EGFR突变体PC 9细胞中出现耐药群体方面显示出显著的效力。这种耐受性与改变的表观遗传状态有关，BRD 9与染色质的结合减少，这与ALDH 1A 1的表达减少有关，ALDH 1A 1是一种先前显示在药物耐受性中重要的基因。因此，BRD 9抑制剂可能在预防表观遗传学定义的耐药性方面表现出实用性。(C)2017爱思唯尔有限公司版权所有
Bromodomain-containing protein 9 (BRD9), an epigenetic "reader" of acetylated lysines on post-translationally modified histone proteins, is upregulated in multiple cancer cell lines. To assess the functional role of BRD9 in cancer cell lines, we identified a small-molecule inhibitor of the BRD9 bromodomain. Starting from a pyrrolopyridone lead, we used structure-based drug design to identify a potent and highly selective in vitro tool compound 11, (GNE-375). While this compound showed minimal effects in cell viability or gene expression assays, it showed remarkable potency in preventing the emergence of a drug tolerant population in EGFR mutant PC9 cells treated with EGFR inhibitors. Such tolerance has been linked to an altered epigenetic state, and 11 decreased BRD9 binding to chromatin, and this was associated with decreased expression of ALDH1A1, a gene previously shown to be important in drug tolerance. BRD9 inhibitors may therefore show utility in preventing epigenetically-defined drug resistance. (C) 2017 Elsevier Ltd. All rights reserved.