A credit-card library approach for disrupting protein-protein interactions
A credit-card library approach for disrupting protein-protein interactions
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DOI：
10.1016/j.bmc.2005.11.052
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发表时间：
2006-04-15
影响因子：
3.5
通讯作者：
Janda, KD
中科院分区：
文献类型：
--
作者：
Xu, Y;Shi, J;Janda, KD
蛋白质-蛋白质界面在许多治疗上重要的靶点中是突出的。利用有机小分子来破坏蛋白质-蛋白质相互作用是化学生物学中当前的挑战。蛋白质-蛋白质相互作用的一个重要例子是Myc蛋白，它在人类癌症中经常被失调。Myc属于碱性螺旋-环-螺旋亮氨酸拉链（bHLH-ZIP）转录因子家族。它仅作为与bHLH-ZIP蛋白Max的异二聚体具有生物活性。在此，我们报告了一种新的策略，已证实通过设计和合成的一个小的平行库组成的“信用卡”化合物的蛋白质-蛋白质相互作用的破坏。这些化合物衍生自平面的芳香族支架，并以四个多样性点官能化。从285元文库中，获得了几个破坏c-Myc-Max相互作用和c-Myc细胞功能的命中。对于这种小的聚焦文库确定的用于破坏Myc-Max二聚化的IC 50值是相当有效的，特别是因为蛋白质-蛋白质相互作用的小分子拮抗剂是众所周知的难以找到。此外，几种化合物在细胞水平上是有活性的，如它们在鸡胚成纤维细胞测定中对Myc作用的生物学效应所示。根据我们的研究结果，这种方法被认为是一个有价值的除了正在开发的新分子与蛋白质-蛋白质界面相互作用的医疗设备。最后，这种破坏蛋白质-蛋白质相互作用的策略应该证明适用于其他蛋白质家族。(c)2005爱思唯尔有限公司保留所有权利。
Protein-protein interfaces are prominent in many therapeutically important targets. Using small organic molecules to disrupt protein-protein interactions is a current challenge in chemical biology. An important example of protein-protein interactions is provided by the Myc protein, which is frequently deregulated in human cancers. Myc belongs to the family of basic helix-loop-helix leucine zipper (bHLH-ZIP) transcription factors. It is biologically active only as heterodimer with the bHLH-ZIP protein Max. Herein, we report a new strategy for the disruption of protein-protein interactions that has been corroborated through the design and synthesis of a small parallel library composed of 'credit-card' compounds. These compounds are derived from a planar, aromatic scaffold and functionalized with four points of diversity. From a 285 membered library, several hits were obtained that disrupted the c-Myc-Max interaction and cellular functions of c-Myc. The IC50 values determined for this small focused library for the disruption of Myc-Max dimerization are quite potent, especially since small molecule antagonists of protein-protein interactions are notoriously difficult to find. Furthermore, several of the compounds were active at the cellular level as shown by their biological effects on Myc action in chicken embryo fibroblast assays. In light of our findings, this approach is considered a valuable addition to the armamentarium of new molecules being developed to interact with protein-protein interfaces. Finally, this strategy for disrupting protein-protein interactions should prove applicable to other families of proteins. (c) 2005 Elsevier Ltd. All rights reserved.