Suppression of RUNX1/ETO oncogenic activity by a small molecule inhibitor of tetramerization
Suppression of RUNX1/ETO oncogenic activity by a small molecule inhibitor of tetramerization
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DOI：
10.3324/haematol.2016.161570
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发表时间：
2017-05
期刊：
影响因子：
10.1
通讯作者：
J. Schanda;Chun-Wei Lee;K. Wohlan;U. Müller-Kuller;H. Kunkel;I. Coco;S. Stein;A. Metz;J. Koch;J. Lausen;U. Platzbecker;H. Medyouf;H. Gohlke;M. Heuser;M. Eder;M. Grez;M. Scherr;C. Wichmann
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文献类型：
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作者：
J. Schanda;Chun-Wei Lee;K. Wohlan;U. Müller-Kuller;H. Kunkel;I. Coco;S. Stein;A. Metz;J. Koch;J. Lausen;U. Platzbecker;H. Medyouf;H. Gohlke;M. Heuser;M. Eder;M. Grez;M. Scherr;C. Wichmann
RUNX 1/ETO是t（8;21）染色体易位的产物，是急性髓性白血病（AML）最常见形式之一的发作和维持所必需的。RUNX 1/ETO具有模块化结构，除了DNA结合结构域（Runt）之外，还包含四个进化上保守的功能结构域，称为神经同源区1-4（NHR 1至NHR 4）。NHR结构域充当各种不同蛋白质的对接位点，此外，NHR 2结构域通过疏水和离子/极性相互作用介导四聚化。四聚化对于RUNX 1/ETO致癌活性是必需的。RUNX 1/ETO高分子量复合物的去稳定化消除了RUNX 1/ETO致癌活性。使用基于结构的虚拟筛选，我们鉴定了几种模拟内四聚化热点的小分子抑制剂，
RUNX1/ETO, the product of the t(8;21) chromosomal translocation, is required for the onset and maintenance of one of the most common forms of acute myeloid leukemia (AML). RUNX1/ETO has a modular structure and, besides the DNA-binding domain (Runt), contains four evolutionary conserved functional domains named nervy homology regions 1-4 (NHR1 to NHR4). The NHR domains serve as docking sites for a variety of different proteins and, in addition, the NHR2 domain mediates tetramerization through hydrophobic and ionic/polar interactions. Tetramerization is essential for RUNX1/ETO oncogenic activity. Destabilization of the RUNX1/ETO high molecular weight complex abrogates RUNX1/ETO oncogenic activity. Using structure-based virtual screening, we identified several small molecule inhibitors mimicking the tetramerization hot spot within