| Autor: |
Margarida Espadinha, Elizabeth A. Lopes, Vanda Marques, Joana D. Amaral, Daniel J.V.A. dos Santos, Mattia Mori, Simona Daniele, Rebecca Piccarducci, Elisa Zappelli, Claudia Martini, Cecília M.P. Rodrigues, Maria M.M. Santos |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
European Journal of Medicinal Chemistry. 241:114637 |
| ISSN: |
0223-5234 |
| DOI: |
10.1016/j.ejmech.2022.114637 |
| Popis: |
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 IC |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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