title: Reactivation of wild-type and mutant p53 by tryptophanolderived oxazoloisoindolinone SLMP53-1, a novel anticancer small-molecule.
abstract: Restoration of the p53 pathway, namely by reactivation of mutant (mut) p53, represents a valuable anticancer strategy. Herein, we report the identification of the enantiopure tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a novel reactivator of wild-type (wt) and mut p53, using a yeast-based screening strategy. SLMP53-1 has a p53-dependent anti-proliferative activity in human wt and mut p53R280K-expressing tumor cells. Additionally, SLMP53-1 enhances p53 transcriptional activity and restores wt-like DNA binding ability to mut p53R280K. In wt/mut p53-expressing tumor cells, SLMP53-1 triggers p53 transcription-dependent and mitochondrial apoptotic pathways involving BAX, and wt/mut p53 mitochondrial translocation. SLMP53-1 inhibits the migration of wt/mut p53-expressing tumor cells, and it shows promising p53-dependent synergistic effects with conventional chemotherapeutics. In xenograft mice models, SLMP53-1 inhibits the growth of wt/mut p53-expressing tumors, but not of p53-null tumors, without apparent toxicity. Collectively, besides the potential use of SLMP53-1 as anticancer drug, the tryptophanol-derived oxazoloisoindolinone scaffold represents a promissing starting point for the development of effective p53-reactivating drugs.
authors.affiliation: UCIBIO/REQUIMTE, Universidade do Porto, Porto, Portugal.|Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Soares
authors.affiliation: UCIBIO/REQUIMTE, Universidade do Porto, Porto, Portugal.|Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
authors.forename: Liliana
authors.initials: L
authors.lastname: Raimundo
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Nuno A L
authors.initials: NA
authors.lastname: Pereira
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Ângelo
authors.initials: Â
authors.lastname: Monteiro
authors.affiliation: UCIBIO/REQUIMTE, Universidade do Porto, Porto, Portugal.|Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Gomes
authors.affiliation: UCIBIO/REQUIMTE, Universidade do Porto, Porto, Portugal.|Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
authors.forename: Cláudia
authors.initials: C
authors.lastname: Bessa
authors.affiliation: UCIBIO/REQUIMTE, Universidade do Porto, Porto, Portugal.|Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
authors.forename: Clara
authors.initials: C
authors.lastname: Pereira
authors.affiliation: Laboratório de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
authors.forename: Glória
authors.initials: G
authors.lastname: Queiroz
authors.affiliation: CIBIO, Centre for Integrative Biology, Laboratory of Transcriptional Networks, University of Trento, Trento, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bisio
authors.affiliation: Laboratório de Farmacologia e Terapêutica Experimental, IBILI, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Fernandes
authors.affiliation: Laboratório de Farmacologia e Terapêutica Experimental, IBILI, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.
authors.forename: Célia
authors.initials: C
authors.lastname: Gomes
authors.affiliation: Laboratório de Farmacologia e Terapêutica Experimental, IBILI, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.
authors.forename: Flávio
authors.initials: F
authors.lastname: Reis
authors.affiliation: Laboratório de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Gonçalves
authors.affiliation: CIBIO, Centre for Integrative Biology, Laboratory of Transcriptional Networks, University of Trento, Trento, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Inga
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Maria M M
authors.initials: MM
authors.lastname: Santos
authors.affiliation: UCIBIO/REQUIMTE, Universidade do Porto, Porto, Portugal.|Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
authors.forename: Lucília
authors.initials: L
authors.lastname: Saraiva
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057166:High-Throughput Screening Assays; D006801:Humans; D007124:Immunoenzyme Techniques; D054833:Isoindoles / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D010080:Oxazoles / Q000737:chemistry* / Q000494:pharmacology*; D010881:Piperidones / Q000737:chemistry*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000737:chemistry; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D054833:Isoindoles; C000605896:OXAZ-1 compound; D010080:Oxazoles; D010881:Piperidones; D012333:RNA, Messenger; C000611864:SLMP53-1 compound; D054852:Small Molecule Libraries; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C069544:tryptophanol; D014364:Tryptophan
keywords: anticancer chemotherapy; mutant; p53; tryptophanol-derived oxazoloisoindolinones; tumor