Selective inhibition of c-Myc/Max dimerization and DNA binding by small molecules
Selective inhibition of c-Myc/Max dimerization and DNA binding by small molecules
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DOI：
10.1016/j.chembiol.2006.05.011
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发表时间：
2006-07-01
影响因子：
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通讯作者：
Berg, Thorsten
中科院分区：
文献类型：
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作者：
Kiessling, Anke;Sperl, Bianca;Berg, Thorsten
bZip和bHLHZip蛋白家族成员包含大部分真核转录因子，并且需要结合DNA以发挥其大部分基本生物学作用。它们与DNA的结合需要通过α-螺旋结构域进行同源或异源二聚化，而α-螺旋结构域通常不含明显的小分子结合位点。我们已经确定了两种小分子，称为Mycro 1和Mycro 2，它们抑制bHLHZip蛋白c-Myc和Max之间的蛋白质-蛋白质相互作用。Mycros是c-Myc/Max二聚化的第一种抑制剂，已证明其在体外抑制c-Myc的DNA结合优于其他二聚体转录因子。Mycros在低微摩尔浓度范围内抑制c-Myc依赖性增殖、基因转录和致癌转化。我们的数据支持这样的观点，即即使在没有明显的小分子结合口袋的情况下，二聚体转录因子也可以是药物化的。
bZip and bHLHZip protein family members comprise a large fraction of eukaryotic transcription factors and need to bind DNA in order to exert most of their fundamental biological roles. Their binding to DNA requires homo- or heterodimerization via alpha-helical domains, which generally do not contain obvious binding sites for small molecules. We have identified two small molecules, dubbed Mycro1 and Mycro2, which inhibit the protein-protein interactions between the bHLHZip proteins c-Myc and Max. Mycros are the first inhibitors of c-Myc/Max dimerization, which have been demonstrated to inhibit DNA binding of c-Myc with preference over other dimeric transcription factors in vitro. Mycros inhibit c-Myc-dependent proliferation, gene transcription, and oncogenic transformation in the low micromolar concentration range. Our data support the idea that dimeric transcription factors can be druggable even in the absence of obvious small-molecule binding pockets.