DIMP53-1: a novel small-molecule dual inhibitor of p53-MDM2/X interactions with multifunctional p53-dependent anticancer properties

• Autor(a) principal: Soares, Joana
• Data de Publicação: 2017
• Outros Autores: Espadinha, Margarida, Raimundo, Liliana, Ramos, Helena, Gomes, Ana Sara, Gomes, Sara, Loureiro, Joana B., Inga, Alberto, Reis, Flávio, Gomes, Célia, Santos, Maria M. M., Saraiva, Lucília
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10316/108278; https://doi.org/10.1002/1878-0261.12051
• topic: anticancer therapy; MDM2; MDMX; p53; small-molecule; tryptophanol-derived oxazoloisoindolinone; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Proteins; Cell Movement; Cell Proliferation; HCT116 Cells; Humans; Isoindoles; MCF-7 Cells; Mice; Mice, Inbred BALB C; Nuclear Proteins; Oxazoles; Phthalimides; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Rats; Rats, Wistar; Tumor Suppressor Protein p53; Up-Regulation; Xenograft Model Antitumor Assays; Molecular Targeted Therapy

The transcription factor p53 plays a crucial role in cancer development and dissemination, and thus, p53-targeted therapies are among the most encouraging anticancer strategies. In human cancers with wild-type (wt) p53, its inactivation by interaction with murine double minute (MDM)2 and MDMX is a common event. Simultaneous inhibition of the p53 interaction with both MDMs is crucial to restore the tumor suppressor activity of p53. Here, we describe the synthesis of the new tryptophanol-derived oxazoloisoindolinone DIMP53-1 and identify its activity as a dual inhibitor of the p53-MDM2/X interactions using a yeast-based assay. DIMP53-1 caused growth inhibition, mediated by p53 stabilization and upregulation of p53 transcriptional targets involved in cell cycle arrest and apoptosis, in wt p53-expressing tumor cells, including MDM2- or MDMX-overexpressing cells. Importantly, DIMP53-1 inhibits the p53-MDM2/X interactions by potentially binding to p53, in human colon adenocarcinoma HCT116 cells. DIMP53-1 also inhibited the migration and invasion of HCT116 cells, and the migration and tube formation of HMVEC-D endothelial cells. Notably, in human tumor xenograft mice models, DIMP53-1 showed a p53-dependent antitumor activity through induction of apoptosis and inhibition of proliferation and angiogenesis. Finally, no genotoxicity or undesirable toxic effects were observed with DIMP53-1. In conclusion, DIMP53-1 is a novel p53 activator, which potentially binds to p53 inhibiting its interaction with MDM2 and MDMX. Although target-directed, DIMP53-1 has a multifunctional activity, targeting major hallmarks of cancer through its antiproliferative, proapoptotic, antiangiogenic, anti-invasive, and antimigratory properties. DIMP53-1 is a promising anticancer drug candidate and an encouraging starting point to develop improved derivatives for clinical application.