Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization
Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization
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DOI：
10.1073/pnas.1203789109
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发表时间：
2012-07-17
影响因子：
11.1
通讯作者：
Vassilev, Lyubomir T.
中科院分区：
文献类型：
--
作者：
Graves, Bradford;Thompson, Thelma;Vassilev, Lyubomir T.
通过拮抗 p53 负调节因子鼠双微体 (MDM) 2 来激活 p53 肿瘤抑制因子被认为是癌症治疗的一种有吸引力的策略，并且已经开发了几类 p53-MDM2 结合抑制剂。然而，这些化合物不会抑制 p53-MDMX 相互作用，并且在过度表达 MDMX 的肿瘤中它们的有效性可能会受到影响。在这里，我们通过抑制剂驱动的 MDM2 和 MDMX 蛋白同源和/或异二聚化，鉴定出能够有效阻断 p53 与 MDM2 和 MDMX 结合的小分子。结构研究表明，抑制剂通过诱导由二聚小分子核心保持在一起的二聚蛋白复合物的形成，结合并封闭 MDM2 和 MDMX 的 p53 口袋。这种作用模式有效稳定了 p53 并激活了癌细胞中的 p53 信号传导，导致细胞周期停滞和细胞凋亡。双重 MDM2/MDMX 拮抗剂可在高水平 MDMX 存在的情况下恢复 p53 凋亡活性，并可能为 MDMX 过度表达的癌症提供更有效的治疗方式。
Activation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM) 2 has been considered an attractive strategy for cancer therapy and several classes of p53-MDM2 binding inhibitors have been developed. However, these compounds do not inhibit the p53-MDMX interaction, and their effectiveness can be compromised in tumors overexpressing MDMX. Here, we identify small molecules that potently block p53 binding with both MDM2 and MDMX by inhibitor-driven homo- and/or heterodimerization of MDM2 and MDMX proteins. Structural studies revealed that the inhibitors bind into and occlude the p53 pockets of MDM2 and MDMX by inducing the formation of dimeric protein complexes kept together by a dimeric small-molecule core. This mode of action effectively stabilized p53 and activated p53 signaling in cancer cells, leading to cell cycle arrest and apoptosis. Dual MDM2/MDMX antagonists restored p53 apoptotic activity in the presence of high levels of MDMX and may offer a more effective therapeutic modality for MDMX-overexpressing cancers.