Therapeutic considerations for Mdm2: not just a one trick pony.
Therapeutic considerations for Mdm2: not just a one trick pony.
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DOI：
10.1517/17460441.3.11.1309
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发表时间：
2008-11
影响因子：
6.3
通讯作者：
Mayo LD
中科院分区：
文献类型：
--
作者：
Lehman JA;Eitel JA;Batuello CN;Mayo LD
mdm 2原癌基因在许多晚期癌症中升高。Mdm 2蛋白部分通过肿瘤抑制蛋白p53的失活来表现出其致癌特性。最近在抗癌药物设计方面的努力集中在鉴定破坏Mdm 2-p53相互作用的小分子上，希望重新参与p53通路。除了与p53结合外，Mdm 2还与许多参与DNA修复、翻译、代谢活动、肿瘤生长和凋亡的蛋白质复合。需要额外的生化分析来了解Mdm 2如何整合到所有这些细胞过程中。Mdm 2的翻译后修饰可以改变其与许多蛋白质结合的能力。蛋白质结构的变化也可能影响小分子抑制剂有效拮抗Mdm 2的能力。在以前的Mdm 2抑制剂的开发过程中，Mdm 2修饰的复杂性在很大程度上被忽视了。未来的高通量或计算机筛选工作将需要认识到Mdm 2翻译后修饰的重要性。此外，鉴定靶向Mdm 2中其他结构域的分子可以提供一种工具来阻止Mdm 2的其他关键p53非依赖性功能。这些目标为发现新的Mdm 2结合化合物提供了有用的路线图，其治疗效力可能超过其前辈。
The mdm2 proto-oncogene is elevated in numerous late stage cancers. The Mdm2 protein manifests its oncogenic properties in part through inactivation of the tumor suppressor protein p53. Recent efforts in anti-cancer drug design have focused on the identification of small molecules that disrupt the Mdm2-p53 interaction, in hopes of re-engaging the p53 pathway. In addition to binding p53, Mdm2 complexes with numerous proteins involved in DNA repair, translation, metabolic activities, tumor growth and apoptosis. Additional biochemical analysis is required to understand how Mdm2 integrates into all of these cellular processes. Post-translational modifications to Mdm2 can alter its ability to associate with numerous proteins. Changes in protein structure may also affect the ability of small molecule inhibitors to effectively antagonize Mdm2. The complexity of Mdm2 modification has been largely neglected during the development of previous Mdm2 inhibitors. Future high-throughput or in silico screening efforts will need to recognize the importance of post-translational modifications to Mdm2. Furthermore, the identification of molecules that target other domains in Mdm2 may provide a tool to prevent other pivotal p53-independent functions of Mdm2. These aims provide a useful roadmap for the discovery of new Mdm2 binding compounds with therapeutic potency that may exceed its predecessors.
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