Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry?
Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry?
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DOI：
10.1158/1541-7786.mcr-08-0423
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发表时间：
2009-01
期刊：
影响因子：
--
通讯作者：
Wahl GM
中科院分区：
文献类型：
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作者：
Wade M;Wahl GM
人类肿瘤样品和肿瘤衍生细胞系的基因组和蛋白质组分析对于实现肿瘤学中的个性化治疗是必不可少的。确定肿瘤发生或维持所需的变化可能会为小分子和生物治疗提供新的靶点。例如，p53肿瘤抑制途径的失活发生在大多数人类癌症中。虽然这可能是由于坦率的p53基因突变，但几乎一半的癌症保留了野生型p53等位基因，表明该途径通过其他方式被禁用。替代机制包括p53阳性调节因子arf的缺失或表观遗传失活、p53启动子的甲基化或p53调节因子Mdm 2和Mdmx的表达升高。本综述讨论了目前的模型，p53的MDM 2和MDMX的调节，并提出了合理的设计未来MDMX特异性治疗的基础上，我们的知识，其结构和生物学功能。为了简单起见，我们在整个综述中使用Mdmx，尽管该蛋白在小鼠中也称为Mdm 4，在人类中也称为Hdmx/Hdm 4。关于Mdm 2作为致癌基因和化疗靶点的更详细讨论可以在其他地方找到。
Genomic and proteomic profiling of human tumor samples and tumor-derived cell lines are essential for the realization of personalized therapy in oncology. Identification of the changes required for tumor initiation or maintenance will likely provide new targets for small molecule and biologic therapeutics. For example, inactivation of the p53 tumor suppressor pathway occurs in most human cancers. While this can be due to frank p53 gene mutation, almost half of all cancers retain the wild type p53 allele, indicating the pathway is disabled by other means. Alternate mechanisms include deletion or epigenetic inactivation of the p53 positive regulator, arf, methylation of the p53 promoter or elevated expression of the p53 regulators Mdm2 and Mdmx. This review discusses current models of p53 regulation by Mdm2 and Mdmx, and presents the rationale for design of future Mdmx-specific therapeutics based on our knowledge of its structure and biological functions. For simplicity, we use Mdmx throughout this review although the protein is also known as Mdm4 in mouse and Hdmx/Hdm4 in humans. A more detailed discussion of Mdm2 as an oncogene and as a target for chemotherapy can be found elsewhere.