Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells
Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells
复制标题
基于结构的 MDM2/4 双重抑制剂的发现，对 MDM4 过表达的癌细胞发挥抗肿瘤活性
DOI：
10.1021/acs.jmedchem.2c00095
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发表时间：
2022
影响因子：
7.3
通讯作者：
Zhao Yujun
中科院分区：
文献类型：
--
作者：
Zhang Shiyan;Yan Ziqin;Li Yafang;Gong Yang;Lyu Xilin;Lou Jianfeng;Zhang Daizhou;Meng Xiangjing;Zhao Yujun
尽管最近基于多肽的MDM2/4双重抑制剂取得了临床进展，但具有强大抗肿瘤活性的小分子抑制剂仍然具有挑战性。为了解决这一问题，我们基于结构设计合成了31 (YL93)，其MDM2/4结合Ki值分别为1.1和642 nM。在三种携带野生型p53的mdm4过表达的癌细胞系中，在后期临床试验中，与mdm2选择性抑制剂RG7388相比，31显示出更好的细胞生长抑制活性。机制研究表明，在MDM4扩增的RKO细胞中，31增加了p53和p21的细胞蛋白水平，上调了p53靶向基因的表达。此外，在western blot和流式细胞术检测中，31个诱导细胞周期阻滞和凋亡。综上所述，与选择性MDM2抑制剂相比，31对MDM2/4的双重抑制在体外对野生型p53和过表达MDM2的癌细胞具有更强的抗肿瘤活性。
Despite recent clinical progress in peptide-based dual inhibitors of MDM2/4, small-molecule ones with robust antitumor activities remain challenging. To tackle this issue, 31 (YL93) was structure-based designed and synthesized, which had MDM2/4 binding Ki values of 1.1 and 642 nM, respectively. In three MDM4-overexpressing cancer cell lines harboring wild-type p53, 31 shows improved cell growth inhibition activities compared to RG7388, an MDM2-selective inhibitor in late-stage clinical trials. Mechanistic studies show that 31 increased cellular protein levels of p53 and p21 and upregulated the expression of p53-targeted genes in RKO cells with MDM4 amplification. In addition, 31 induced cell-cycle arrest and apoptosis in western blot and flow cytometry assays. Taken together, dual inhibition of MDM2/4 by 31 elicited stronger antitumor activities in vitro compared to selective MDM2 inhibitors in wild-type p53 and MDM4-overexpressing cancer cells.