Clinical Overview of MDM2/X-Targeted Therapies.
Clinical Overview of MDM2/X-Targeted Therapies.
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MDM2/X 靶向治疗的临床概述。
DOI：
10.3389/fonc.2016.00007
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发表时间：
2016
影响因子：
4.7
通讯作者：
Lim E
中科院分区：
文献类型：
--
作者：
Burgess A;Chia KM;Haupt S;Thomas D;Haupt Y;Lim E
MDM2和MDMX是P53的主要负调控因子，在正常情况下，它们通过靶向蛋白酶体快速降解并抑制其转录活性来维持细胞内低水平的P53。MDM2和MDMX都是强大的癌基因，在一些癌症中普遍过度表达，包括肉瘤(~20%)和乳腺癌(~15%)。与p53突变的肿瘤不同，目前的治疗策略恢复了p53的正常活性构象，MDM2和MDMX是癌症中增加野生型(WT)p53表达和活性的合理治疗靶点。最近的临床前研究表明，也可能存在MDM2/X抑制剂用于p53突变肿瘤的情况。自从发现了Nutlin-3a以来，现在已经有了一系列相关化合物的广泛清单。Nutlin-3a是第一种小分子MDM2抑制剂，它与MDM2 N端的疏水裂隙结合，阻止了它与p53的结合。此外，还开发了一类既可以针对MDM2又可以针对MDMX的新型装订多肽。重要的是，临床前建模已经证明了在体外和体内有效地杀死WT-P53癌细胞，现在已经转化为早期临床试验，从而能够更好地评估它们对患者的生物学效应和毒性。在这篇综述中，我们将回顾目前正在开发的MDM2和MDMX靶向疗法，特别是已经进入早期临床试验的化合物。我们将重点介绍与这些化合物的预测生物标记物和毒性相关的挑战，以及确定潜在的组合策略，以增强其抗癌效果。
MDM2 and MDMX are the primary negative regulators of p53, which under normal conditions maintain low intracellular levels of p53 by targeting it to the proteasome for rapid degradation and inhibiting its transcriptional activity. Both MDM2 and MDMX function as powerful oncogenes and are commonly over-expressed in some cancers, including sarcoma (~20%) and breast cancer (~15%). In contrast to tumors that are p53 mutant, whereby the current therapeutic strategy restores the normal active conformation of p53, MDM2 and MDMX represent logical therapeutic targets in cancer for increasing wild-type (WT) p53 expression and activities. Recent preclinical studies suggest that there may also be situations that MDM2/X inhibitors could be used in p53 mutant tumors. Since the discovery of nutlin-3a, the first in a class of small molecule MDM2 inhibitors that binds to the hydrophobic cleft in the N-terminus of MDM2, preventing its association with p53, there is now an extensive list of related compounds. In addition, a new class of stapled peptides that can target both MDM2 and MDMX have also been developed. Importantly, preclinical modeling, which has demonstrated effective in vitro and in vivo killing of WT p53 cancer cells, has now been translated into early clinical trials allowing better assessment of their biological effects and toxicities in patients. In this overview, we will review the current MDM2- and MDMX-targeted therapies in development, focusing particularly on compounds that have entered into early phase clinical trials. We will highlight the challenges pertaining to predictive biomarkers for and toxicities associated with these compounds, as well as identify potential combinatorial strategies to enhance its anti-cancer efficacy.