Low molecular weight inhibitors of Myc-Max interaction and function
Low molecular weight inhibitors of Myc-Max interaction and function
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DOI：
10.1038/sj.onc.1206641
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发表时间：
2003-09-18
期刊：
影响因子：
8
通讯作者：
Prochownik, EV
中科院分区：
文献类型：
--
作者：
Yin, XY;Giap, C;Prochownik, EV
c-Myc是螺旋-环-螺旋-亮氨酸拉链（HLH-ZIP）癌蛋白，其在人类癌症中经常失调。为了结合DNA，调节靶基因表达，并在生物学背景下发挥功能，c-Myc必须与另一种HLH-ZIP蛋白Max二聚化。已经鉴定了大量的c-Myc靶基因，并且许多编码的蛋白质正在转化。然而，这种功能冗余使旨在抑制任何单一靶基因产物的治疗策略复杂化。考虑到这一点，我们转而试图确定c-Myc本身可以有效失活的方法。我们已经使用酵母双杂交方法来鉴定抑制c-Myc - Max缔合的低分子量化合物。所有的化合物阻止c-Myc - Max异二聚体的反式激活，抑制细胞周期的进展，并阻止成纤维细胞在体外生长的c-Myc依赖性的方式。几种化合物也抑制体内肿瘤生长。这些结果表明，酵母双杂交筛选可用于鉴定可在哺乳动物细胞中利用的化合物。更具体地说，它们提供了一种方法，通过这种方法，可以开发基于这些第一代Myc-Max抑制剂的结构类似物，以增强抗肿瘤功效。
c-Myc is helix - loop - helix - leucine zipper (HLH-ZIP) oncoprotein that is frequently deregulated in human cancers. In order to bind DNA, regulate target gene expression, and function in a biological context, c-Myc must dimerize with another HLH - ZIP protein, Max. A large number of c-Myc target genes have been identified, and many of the encoded proteins are transforming. Such functional redundancy, however, complicates therapeutic strategies aimed at inhibiting any single target gene product. Given this consideration, we have instead attempted to identify ways by which c-Myc itself could be effectively disabled. We have used a yeast two-hybrid approach to identify low-molecular-weight compounds that inhibit c-Myc - Max association. All of the compounds prevented transactivation by c-Myc - Max heterodimers,inhibited cell cycle progression, and prevented the in vitro growth of fibroblasts in a c-Myc-dependent manner. Several of the compounds also inhibited tumor growth in vivo. These results show that the yeast two-hybrid screen is useful for identifying compounds that can be exploited in mammalian cells. More specifically, they provide a means by which structural analogs, based upon these first-generation Myc-Max inhibitors, can be developed to enhance antitumor efficacy.