Recent advances in validating MDM2 as a cancer target.
Recent advances in validating MDM2 as a cancer target.
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DOI：
10.2174/187152009789124628
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发表时间：
2009-10
影响因子：
2.8
通讯作者：
Zhang R
中科院分区：
文献类型：
--
作者：
Rayburn ER;Ezell SJ;Zhang R
MDM2致癌基因在各种人类癌症中过度表达。它的表达与高级别、晚期和更耐药的肿瘤的表型相关。长期以来，MDM2和肿瘤抑制因子p53之间的自调节环一直被认为是癌症治疗合理靶点的缩影。因此，已经产生了许多新的药物来干扰这两种蛋白质的相互作用，从而导致p53的激活。在这些药物中有几种基于MDM2-p53复合物的晶体结构合成的小分子抑制剂。通过高通量筛选，发现了几种特异性和有效的抑制蛋白-蛋白相互作用的药物。然而，最近的研究表明，许多蛋白质调节MDM2-p53相互作用，MDM2可能具有p53独立的致癌功能。为了使新的MDM2抑制剂转化为临床，有必要更好地了解MDM2的调控以及MDM2-p53的相互作用。特别是，需要阐明某些调节因子与MDM2/p53在不同情况下的各种相互作用的含义，以确定哪些途径代表了最佳的治疗靶点。针对MDM2本身和MDM2的调节因子以及MDM2-p53相互作用，或将MDM2抑制剂与常规治疗联合使用，可能会改善肿瘤根除的前景。
The MDM2 oncogene is overexpressed in various human cancers. Its expression correlates with the phenotypes of high-grade, late-stage, and more resistant tumors. The auto-regulatory loop between MDM2 and the tumor suppressor p53 has long been considered the epitome of a rational target for cancer therapy. As such, many novel agents have been generated to interfere with the interaction of the two proteins, which results in the activation of p53. Among these agents are several small molecule inhibitors synthesized based upon the crystal structures of the MDM2-p53 complex. With use of high-throughput screening, several specific and effective agents for inhibition of the protein-protein interaction were discovered. Recent investigations, however, have demonstrated that many proteins regulate the MDM2-p53 interaction, and that MDM2 may have p53-independent oncogenic functions. In order for novel MDM2 inhibitors to be translated to the clinic, it is necessary to obtain a better understanding of the regulation of MDM2 and of the MDM2-p53 interaction. In particular, the implications of various interactions between certain regulator(s) and MDM2/p53 under different circumstances need to be elucidated to determine which pathway(s) represent the best targets for therapy. Targeting both MDM2 itself and regulators of MDM2 and the MDM2-p53 interaction, or use of MDM2 inhibitors in combination with conventional treatments, may improve prospects for tumor eradication.
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