Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells,Journal of Medicinal Chemistry

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Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-04-14 , DOI: 10.1021/acs.jmedchem.2c00095
Shiyan Zhang _{1,

2} , Ziqin Yan ₁ , Yafang Li _{1,

3} , Yang Gong _{1,

4} , Xilin Lyu ₁ , Jianfeng Lou _{1,

2} , Daizhou Zhang ₅ , Xiangjing Meng ₅ , Yujun Zhao _{1,

2,

4,

5,

6}

Affiliation

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 K_i 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.

中文翻译：

基于结构的 MDM2/4 双抑制剂的发现对 MDM4 过表达的癌细胞具有抗肿瘤活性

尽管最近在基于肽的 MDM2/4 双重抑制剂方面取得了临床进展，但具有强大抗肿瘤活性的小分子抑制剂仍然具有挑战性。为了解决这个问题，31 ( YL93 ) 基于结构设计和合成，其 MDM2/4 结合K _i值分别为 1.1 和 642 nM。在三个含有野生型 p53 的过表达 MDM4 的癌细胞系中，31与 RG7388（一种晚期临床试验中的 MDM2 选择性抑制剂）相比，显示出改善的细胞生长抑制活性。机制研究表明，31增加了 p53 和 p21 的细胞蛋白水平，并通过 MDM4 扩增上调了 RKO 细胞中 p53 靶向基因的表达。此外，31在蛋白质印迹和流式细胞术测定中诱导细胞周期停滞和细胞凋亡。总之，与野生型 p53 和 MDM4 过表达癌细胞中的选择性 MDM2 抑制剂相比， 31对 MDM2/4 的双重抑制在体外引发了更强的抗肿瘤活性。

更新日期：2022-04-14

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