Novel dual inhibitor of the p53-MDM2/X interactions with anticancer properties

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Novel dual inhibitor of the p53-MDM2/X interactions with anticancer properties

Friday, 06.04.2018

Considering the crucial role of p53 in cancer development and dissemination, p53-targeted therapies are amongst the most encouraging anticancer strategies. Inactivation of p53 by interaction with murine double minute (MDM)2 and MDMX is a common event in human cancers bearing wild-type (wt) p53. Consistently, simultaneous inhibition of the p53 interaction with both MDMs is crucial for full p53 reactivation in cancer. In this work, the new tryptophanol-derived oxazoloisoindolinone DIMP53-1 was synthesized, and its activity as a dual inhibitor of the p53-MDM2/X interactions was identified using a yeast-based assay. Consistently, 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 abolishes the p53-MDM2/X interactions by 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 anti-proliferative, pro-apoptotic, anti-angiogenic, anti-invasive and anti-migratory properties. DIMP53-1 is a promising anticancer drug candidate and an encouraging starting point to develop improved derivatives for clinical application.


Joana Soares (a,b), Margarida Espadinha (c), Liliana Raimundo (a,b), Helena Ramos (a,b), Ana Sara Gomes (a,b), Sara Gomes (a,b), Joana B. Loureiro (a,b), Alberto Inga (d), Flávio Reis (e), Célia Gomes (e), Maria M.M. Santos (c), Lucília Saraiva (a,b)

(a) UCIBIO/REQUIMTE,

(b) Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal

(c) Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal

(d) CIBIO, Centre for Integrative Biology, Laboratory of Transcriptional Networks, University of Trento, Trento, Italy

(e) Laboratório de Farmacologia e Terapêutica Experimental, Instituto de Imagem Biomédica e Ciências da Vida (IBILI), Faculdade de Medicina; e Consórcio CNC.IBILI, Universidade de Coimbra, Coimbra, Portugal

 

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.

Molecular Oncology

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467495/