title: Discovery of a new small-molecule inhibitor of p53-MDM2 interaction using a yeast-based approach.
abstract: The virtual screening of a library of xanthone derivatives led us to the identification of potential novel MDM2 ligands. The activity of these compounds as inhibitors of p53-MDM2 interaction was investigated using a yeast phenotypic assay, herein developed for the initial screening. Using this approach, in association with a yeast p53 transactivation assay, the pyranoxanthone (3,4-dihydro-12-hydroxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthen-6-one) (1) was identified as a putative small-molecule inhibitor of p53-MDM2 interaction. The activity of the pyranoxanthone 1 as inhibitor of p53-MDM2 interaction was further investigated in human tumor cells with wild-type p53 and overexpressed MDM2. Notably, the pyranoxanthone 1 mimicked the activity of known p53 activators, leading to p53 stabilization and activation of p53-dependent transcriptional activity. Additionally, it led to increased protein levels of p21 and Bax, and to caspase-7 cleavage. By computational docking studies, it was predicted that, like nutlin-3a, a known small-molecule inhibitor of p53-MDM2 interaction, pyranoxanthone 1 binds to the p53-binding site of MDM2. Overall, in this work, a novel small-molecule inhibitor of p53-MDM2 interaction with a xanthone scaffold was identified for the first time. Besides its potential use as molecular probe and possible lead to develop anticancer agents, the pyranoxanthone 1 will pave the way for the structure-based design of a new class of p53-MDM2 inhibitors.
authors: REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira n.° 164, 4050-313 Porto, Portugal.
authors: Mariana
authors: M
authors: Leão
authors: Clara
authors: C
authors: Pereira
authors: Alessandra
authors: A
authors: Bisio
authors: Yari
authors: Y
authors: Ciribilli
authors: Ana M
authors: AM
authors: Paiva
authors: Neuza
authors: N
authors: Machado
authors: Andreia
authors: A
authors: Palmeira
authors: Miguel X
authors: MX
authors: Fernandes
authors: Emília
authors: E
authors: Sousa
authors: Madalena
authors: M
authors: Pinto
authors: Alberto
authors: A
authors: Inga
authors: Lucília
authors: L
authors: Saraiva
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D057166:High-Throughput Screening Assays; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014966:Xanthenes / Q000737:chemistry* / Q000494:pharmacology; D044004:Xanthones / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C581162:3,4-dihydro-12-hydroxy-2,2-dimethyl-2H,6H-pyrano(3,2-b)xanthen-6-one; D000970:Antineoplastic Agents; D001578:Benzopyrans; D016159:Tumor Suppressor Protein p53; D014966:Xanthenes; D044004:Xanthones; D051736:Proto-Oncogene Proteins c-mdm2