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

Abstract

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.

• Authors: Joana Soares, Margarida Espadinha, Liliana Raimundo, Helena Ramos, Ana Sara Gomes, Sara Gomes, Joana B Loureiro, Alberto Inga, Flávio Reis, Célia Gomes, Maria M M Santos, Lucília Saraiva
• Journal: Molecular oncology (Mol Oncol) Vol. 11 Issue 6 Pg. 612-627 (06 2017) ISSN: 1878-0261 [Electronic] United States
• PMID: 28296148 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Cell Cycle Proteins
• DIMP53-1
• Isoindoles
• MDM4 protein, human
• Nuclear Proteins
• Oxazoles
• Phthalimides
• Proto-Oncogene Proteins
• TP53 protein, human
• Tumor Suppressor Protein p53
• phthalimidine
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Angiogenesis Inhibitors (chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Cycle Proteins
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• HCT116 Cells
• Humans
• Isoindoles (chemistry, pharmacology)
• MCF-7 Cells
• Mice
• Mice, Inbred BALB C
• Molecular Targeted Therapy
• Nuclear Proteins (antagonists & inhibitors, metabolism)
• Oxazoles (chemistry, pharmacology)
• Phthalimides (chemistry, pharmacology)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, metabolism)
• Rats
• Rats, Wistar
• Tumor Suppressor Protein p53 (antagonists & inhibitors, metabolism)
• Up-Regulation
• Xenograft Model Antitumor Assays