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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization
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Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization

机译：小分子诱导的MDM2和MDMX二聚化激活p53途径

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摘要

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 pS3 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.
机译：通过拮抗p53肿瘤抑制因子鼠双分钟（MDM）2的激活已被认为是一种有吸引力的癌症治疗策略，并且已经开发出多种类型的p53-MDM2结合抑制剂。但是，这些化合物不会抑制p53-MDMX相互作用，并且在过表达MDMX的肿瘤中可能会削弱其有效性。在这里，我们确定了通过抑制剂驱动的MDM2和MDMX蛋白的均二和/或异二聚作用，有效阻断p53与MDM2和MDMX结合的小分子。结构研究表明，抑制剂通过诱导二聚体小分子核心保持在一起的二聚体蛋白复合物的形成，结合并封闭了MDM2和MDMX的p53口袋。这种作用方式有效地稳定了癌细胞中的p53和激活的pS3信号，导致细胞周期停滞和凋亡。两种MDM2 / MDMX拮抗剂在高水平MDMX的存在下恢复了p53的凋亡活性，可能为过表达MDMX的癌症提供更有效的治疗方法。

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    Bradford Graves; Thelma Thompson; Mingxuan Xia; Cheryl Janson; Christine Lukacs; Dayanand Deo; Paola Di Lello; David Fry; Colin Garvie; Kuo-Sen Huang; Lin Gao; Christian Tovar; Allen Lovey; Jutta Wanner; LyubomirT. Vassilev;

  • 作者单位

    Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;

    Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;

    Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;

    Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;

    Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;

    Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;

    Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;

    Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;

    Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;

    Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;

    Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;

    Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;

    Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;

    Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;

    Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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