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.

Improving anticancer activity towards colon cancer cells with a new p53‐activating agent

“…As a characteristic of human cancer is the suppression of the p53 pathway, the activation of this pathway has become one of the most attractive therapeutic strategies against cancer. In earlier work, we demonstrated the ability of enantiopure tryptophanol-derived oxazoloisoindolinones, namely, SLMP53-1 (Soares et al, 2016) and DIMP53-1 (Soares et al, 2017) to activate p53. In the present work, we developed a novel (R)-tryptophanol-derived bicyclic lactam, the compound SYNAP, that was found to act as a p53-activating agent.…”

“…In earlier work, we demonstrated the ability of enantiopure tryptophanol‐derived oxazoloisoindolinones, namely, SLMP53–1 (Soares et al, ) and DIMP53–1 (Soares et al, ) to activate p53. In the present work, we developed a novel ( R )‐tryptophanol‐derived bicyclic lactam, the compound SYNAP, that was found to act as a p53‐activating agent.…”

“…Notably, the induction of p53 protein thermal stabilization by SYNAP in cancer cells identified p53 as a putative target of SYNAP. Consistent with these results, a tryptophanol‐derived oxazoloisoindolinone was also recently described as a low MW, p53‐binding compound with the ability to disrupt the p53 interaction with both MDM2 and MDMX (Soares et al, ). These results reinforce the notion that tryptophanol derivatives are promising starting points for the development of new p53‐activating agents, particularly those that are inhibitors of the p53‐MDM2/MDMX interactions.…”

Discovery of a small-molecule protein kinase Cδ-selective activator with promising application in colon cancer therapy

“…Cell migration was analyzed using PKCδ-knockdown and control HCT116 cells, using both the wound healing assay and the QCM 24-Well Fluorimetric Chemotaxis Cell Migration Kit (8 µm; Merck Millipore) 49 , 50 . In the wound healing assay, confluent HCT116 cells with a wound were treated with Roy-Bz or vehicle for up to 48 h. Cells were photographed using the Moticam 5.0MP camera with a Motic’s AE2000 inverted microscope (×100 magnification).…”

Design and Anticancer Activity Prediction of Dihyropyrimidinone Based Novel Inhibitors of P53-Mdm2 Interaction

“…Thus, prevent degradation of p53 and maintain its high level for induction of apoptosis in cancer cells. Earlier, diversity of small molecular inhibitors of p53-MDM2 interaction have been reported such nutlins (nutlin-3a), spirooxindoles (SAR405838), dihydroisoquinolinones (NVP-CGM097), and oxazoloisoindolinones (DIMP53-1) [3][4][5][6]. Most of inhibitors of p53-MDM2 interaction have multiples chiral centers so that their synthesis, as well as purification, is a tedious process.…”