Nuti Elisa, La Pietra Valeria, Daniele Simona, Cuffaro Doretta, Ciccone Lidia, Giacomelli Chiara, Cason Carolina, Carotenuto Alfonso, D'Amore Vincenzo Maria, Pozzo Eleonora Da, Costa Barbara, Di Leo Riccardo, Comar Manola, Marinelli Luciana, Martini Claudia, Rossello Armando
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy.
Pharmaceuticals (Basel). 2022 Oct 26;15(11):1318. doi: 10.3390/ph15111318.
Intracellular pathogens, such as , have been recently shown to induce degradation of p53 during infection, thus impairing the protective response of the host cells. Therefore, p53 reactivation by disruption of the p53-MDM2 complex could reduce infection and restore pro-apoptotic effect of p53. Here, we report the identification of a novel MDM2 inhibitor with potential antitumoural and antibacterial activity able to reactivate p53. A virtual screening was performed on an in-house chemical library, previously synthesised for other targets, and led to the identification of a hit compound with a benzo[a]dihydrocarbazole structure, RM37. This compound induced p53 up-regulation in U343MG glioblastoma cells by blocking MDM2-p53 interaction and reduced tumour cell growth. NMR studies confirmed its ability to dissociate the MDM2-p53 complex. Notably, RM37 reduced infection in HeLa cells in a concentration-dependent manner and ameliorated the inflammatory status associated with infection.
细胞内病原体，如……，最近已被证明在感染过程中会诱导p53降解，从而损害宿主细胞的保护反应。因此，通过破坏p53-MDM2复合物来重新激活p53可以减少感染并恢复p53的促凋亡作用。在此，我们报告鉴定出一种具有潜在抗肿瘤和抗菌活性、能够重新激活p53的新型MDM2抑制剂。对一个内部化学文库进行了虚拟筛选，该文库先前是为其他靶点合成的，结果鉴定出一种具有苯并[a]二氢咔唑结构的命中化合物RM37。该化合物通过阻断MDM2-p53相互作用诱导U343MG胶质母细胞瘤细胞中p53上调，并减少肿瘤细胞生长。核磁共振研究证实了其解离MDM2-p53复合物的能力。值得注意的是，RM37以浓度依赖的方式降低了HeLa细胞中的……感染，并改善了与感染相关的炎症状态。
