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Discovery of MDM2-p53 and MDM4-p53 protein-protein interactions small molecule dual inhibitors
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2022-08-05 , DOI: 10.1016/j.ejmech.2022.114637
Margarida Espadinha 1 , Elizabeth A Lopes 1 , Vanda Marques 1 , Joana D Amaral 1 , Daniel J V A Dos Santos 2 , Mattia Mori 3 , Simona Daniele 4 , Rebecca Piccarducci 4 , Elisa Zappelli 4 , Claudia Martini 4 , Cecília M P Rodrigues 1 , Maria M M Santos 1
Affiliation  

MDM2 and MDM4 are key negative regulators of p53, an important protein involved in several cell processes (e.g. cell cycle and apoptosis). Not surprisingly, the p53 tumor suppressor function is inactivated in tumors overexpressing these two proteins. Therefore, both MDM2 and MDM4 are considered important therapeutic targets for an effective reactivation of the p53 function. Herein, we present our studies on the development of spiropyrazoline oxindole small molecules able to inhibit MDM2/4-p53 protein-protein interactions (PPIs). Twenty-seven potential spiropyrazoline oxindole dual inhibitors were prepared based on in silico structural optimization studies of a hit compound with MDM2 and MDM4 proteins. The antiproliferative activity of the target compounds was evaluated in cancer cell lines harboring wild-type p53 and overexpressing MDM2 and/or MDM4. The most active compounds in SJSA-1 cells, 2q and 3b, induce cell death via apoptosis and control cell growth by targeting the G0/G1 cell cycle checkpoint in a concentration-dependent manner. The ability of the five most active spiropyrazoline oxindoles in dissociating p53 from MDM2 and MDM4 was analyzed by an immunoenzymatic assay. Three compounds inhibited MDM2/4-p53 PPIs with IC50 values in the nM range, while one compound inhibited more selectively the MDM2-p53 PPI over the MDM4-p53 PPI. Collectively, these results show: i) 3b may serve as a valuable lead for obtaining selective MDM2-p53 PPI inhibitors and more efficient anti-osteosarcoma agents; ii) 2a, 2q and 3f may serve as valuable leads for obtaining dual MDM2/4 inhibitors and more effective p53 activators.



中文翻译:

MDM2-p53和MDM4-p53蛋白-蛋白相互作用小分子双重抑制剂的发现

MDM2 和 MDM4 是 p53 的关键负调节因子,p53 是一种参与多种细胞过程(例如细胞周期和细胞凋亡)的重要蛋白质。毫不奇怪,p53 肿瘤抑制功能在过表达这两种蛋白质的肿瘤中失活。因此,MDM2 和 MDM4 都被认为是有效激活 p53 功能的重要治疗靶点。在此,我们介绍了我们对开发能够抑制 MDM2/4-p53 蛋白-蛋白相互作用 (PPI) 的螺吡唑啉羟吲哚小分子的研究。27种潜在的螺吡唑啉羟吲哚双重抑制剂的制备具有 MDM2 和 MDM4 蛋白的命中化合物的结构优化研究。在含有野生型 p53 和过表达 MDM2 和/或 MDM4 的癌细胞系中评估了目标化合物的抗增殖活性。SJSA-1 细胞中最活跃的化合物2q3b通过细胞凋亡诱导细胞死亡,并通过以浓度依赖性方式靶向 G0/G1 细胞周期检查点来控制细胞生长。通过免疫酶测定分析了五种最活跃的螺吡唑啉羟吲哚将 p53 从 MDM2 和 MDM4 中解离的能力。三种化合物抑制 MDM2/4-p53 PPI,IC 50值在 nM 范围内,而一种化合物比 MDM4-p53 PPI 更选择性地抑制 MDM2-p53 PPI。总的来说,这些结果表明:i)3b可作为获得选择性 MDM2-p53 PPI 抑制剂和更有效的抗骨肉瘤药物的宝贵线索;ii) 2a2q3f可作为获得双重 MDM2/4 抑制剂和更有效的 p53 激活剂的有价值的线索。

更新日期:2022-08-09
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