RESUMEN
The tumor suppressor p53 is the most frequently mutated protein in human cancer and tops the list of high-value precision oncology targets. p53 prevents initiation and progression of cancer by inducing cell-cycle arrest and various forms of cell death. Tumors have thus evolved ways to inactivate p53, mainly by TP53 mutations or by hyperactive p53 degradation. This review focuses on two types of p53 targeting compounds, MDM2 antagonists and mutant p53 correctors. MDM2 inhibitors prevent p53 protein degradation, while correctors restore tumor suppressor activity of p53 mutants by enhancing thermodynamic stability. Herein we explore both novel and repurposed p53 targeting compounds, discuss their mode of action, and examine the challenges in advancing them to the clinic.
Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Neoplasias/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/uso terapéutico , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Medicina de Precisión , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Flexible heteroarotinoids (Flex-Hets) are compounds with promising anti-cancer activities. SHetA2, a first-generation Flex-Het, has been shown to inhibit the growth of cervical, head and neck, kidney, lung, ovarian, prostate, and breast cancers. However, SHetA2's high lipophilicity, limited selectivity, low oral bioavailability, and complicated synthesis has led to the development of second-generation compounds, such as 1-(1-(naphthalen-1-yl)ethyl)-3-(4-nitrophenyl) thiourea or SL-1-09. Results from our lab show that SL-1-09 exhibits anti-cancer activities against ERα+ and ERα- breast cancer cells at micromolar concentrations. SL-1-09 is a mixture of two enantiomers, R and S. The objective of this study was to further analyze these enantiomers to determine their individual anti-cancer activities. Cell cycle analysis demonstrated that the percentage of cells in S-phase is reduced significantly when breast cancer cell lines MCF-7, T47D and MDA-MB-453 cells are treated with 5.0 µM of the S enantiomer. Consistent with this finding, treatment of these cells with the S enantiomer resulted in lower expression levels of cell cycle proteins. Overall, our data indicate that the S enantiomer shows greater growth inhibitory effects than the R form against ERα+ (MCF7 and T47D) and ERα- (MDA-MB-453) breast cancer cells, suggesting that the activity observed in SL-1-09 is most likely due to the ability of the S enantiomer to block cell cycle progression.