DIMP 53‐1: a novel small‐molecule dual inhibitor of p53– MDM 2/X interactions with multifunctional p53‐dependent anticancer properties

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 MDM s is crucial to restore the tumor suppressor activity of p53. Here, we describe the synthesis of the new tryptophanol‐derived oxazoloisoindolinone DIMP 53‐1 and identify its activity as a dual inhibitor of the p53– MDM 2/X interactions using a yeast‐based assay. DIMP 53‐1 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 MDM 2‐ or MDMX ‐overexpressing cells. Importantly, DIMP 53‐1 inhibits the p53– MDM 2/X interactions by potentially binding to p53, in human colon adenocarcinoma HCT 116 cells. DIMP 53‐1 also inhibited the migration and invasion of HCT 116 cells, and the migration and tube formation of HMVEC ‐D endothelial cells. Notably, in human tumor xenograft mice models, DIMP 53‐1 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 DIMP 53‐1. In conclusion, DIMP 53‐1 is a novel p53 activator, which potentially binds to p53 inhibiting its interaction with MDM 2 and MDMX . Although target‐directed, DIMP 53‐1 has a multifunctional activity, targeting major hallmarks of cancer through its antiproliferative, proapoptotic, antiangiogenic, anti‐invasive, and antimigratory properties. DIMP 53‐1 is a promising anticancer drug candidate and an encouraging starting point to develop improved derivatives for clinical application.