Heterocyclic Diamidine DNA Ligands as HOXA9 Transcription Factor Inhibitors: Design, Molecular Evaluation, and Cellular Consequences in a HOXA9-Dependant Leukemia Cell Model
Heterocyclic Diamidine DNA Ligands as HOXA9 Transcription Factor Inhibitors: Design, Molecular Evaluation, and Cellular Consequences in a HOXA9-Dependant Leukemia Cell Model
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DOI：
10.1021/acs.jmedchem.8b01448
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发表时间：
2019-02-14
影响因子：
7.3
通讯作者：
David-Cordonnier, Marie-Helene
中科院分区：
文献类型：
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作者：
Depauw, Sabine;Lambert, Melanie;David-Cordonnier, Marie-Helene
由于缺乏直接靶向的结合口袋，大多数转录因子在很长一段时间内被认为是不能下药的靶标。与急性髓系白血病有关的HOXA9就是其中之一。到目前为止，只发展了间接靶向HOXA9表达或多靶点HOX/PBX蛋白/蛋白相互作用抑制剂。作为一种有吸引力的抑制DNA结合的选择，我们选择了一系列杂环二胺作为HOXA9同源序列上的次要凹槽DNA配体作为HOXA9/DNA相互作用的有效竞争者。选定的DB818和DB1055化合物在荧光素酶分析、细胞存活和细胞周期中改变了HOXA9介导的转录，但增加了细胞死亡和粒/单核细胞分化，这两个主要HOXA9功能在DB818处理的小鼠Hoxa9转化的造血细胞的转录分析中也得到了强调。总之，这些数据首次证明了序列选择性DNA配体在体外和小鼠Hoxa9依赖的白血病细胞模型中抑制HOXA9/DNA结合的倾向。
Most transcription factors were for a long time considered as undruggable targets because of the absence of binding pockets for direct targeting. HOXA9, implicated in acute myeloid leukemia, is one of them. To date, only indirect targeting of HOXA9 expression or multitarget HOX/PBX protein/protein interaction inhibitors has been developed. As an attractive alternative by inhibiting the DNA binding, we selected a series of heterocyclic diamidines as efficient competitors for the HOXA9/DNA interaction through binding as minor groove DNA ligands on the HOXA9 cognate sequence. Selected DB818 and DB1055 compounds altered HOXA9-mediated transcription in luciferase assays, cell survival, and cell cycle, but increased cell death and granulocyte/monocyte differentiation, two main HOXA9 functions also highlighted using transcriptomic analysis of DB818-treated murine Hoxa9-transformed hematopoietic cells. Altogether, these data demonstrate for the first time the propensity of sequence-selective DNA ligands to inhibit HOXA9/DNA binding both in vitro and in a murine Hoxa9-dependent leukemic cell model.