title: 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.affiliation: UCIBIO/REQUIMTE, Universidade do Porto, Portugal.|Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Soares
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.
authors.forename: Margarida
authors.initials: M
authors.lastname: Espadinha
authors.affiliation: UCIBIO/REQUIMTE, Universidade do Porto, Portugal.|Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Portugal.
authors.forename: Liliana
authors.initials: L
authors.lastname: Raimundo
authors.affiliation: UCIBIO/REQUIMTE, Universidade do Porto, Portugal.|Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Ramos
authors.affiliation: UCIBIO/REQUIMTE, Universidade do Porto, Portugal.|Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Portugal.
authors.forename: Ana Sara
authors.initials: AS
authors.lastname: Gomes
authors.affiliation: UCIBIO/REQUIMTE, Universidade do Porto, Portugal.|Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Gomes
authors.affiliation: UCIBIO/REQUIMTE, Universidade do Porto, Portugal.|Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Portugal.
authors.forename: Joana B
authors.initials: JB
authors.lastname: Loureiro
authors.affiliation: CIBIO, Centre for Integrative Biology, Laboratory of Transcriptional Networks, University of Trento, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Inga
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Portugal.|Centre for Neuroscience and Cell Biology - Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Consortium, University of Coimbra, Portugal.
authors.forename: Flávio
authors.initials: F
authors.lastname: Reis
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Portugal.|Centre for Neuroscience and Cell Biology - Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Consortium, University of Coimbra, Portugal.
authors.forename: Célia
authors.initials: C
authors.lastname: Gomes
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.
authors.forename: Maria M M
authors.initials: MMM
authors.lastname: Santos
authors.affiliation: UCIBIO/REQUIMTE, Universidade do Porto, Portugal.|Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Portugal.
authors.forename: Lucília
authors.initials: L
authors.lastname: Saraiva
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D054833:Isoindoles / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D010797:Phthalimides / Q000737:chemistry / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C000626504:DIMP53-1; D054833:Isoindoles; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D010080:Oxazoles; D010797:Phthalimides; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C037432:phthalimidine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: 
  MDMX
  ; MDM2; anticancer therapy; p53; small-molecule; tryptophanol-derived oxazoloisoindolinone