Discovery of a new small-molecule inhibitor of p53-MDM2 interaction using a yeast-based approach

• Tipo: Artigo em Revista Científica Internacional
• Data: 2013

Autores

Mariana Leao (Autor) Outra; Clara Pereira (Autor) Outra; Alessandra Bisio (Autor) Outra; Yari Ciribilli (Autor) Outra; Ana M Paiva (Autor) Outra; Neuza Machado (Autor) Outra; Andreia Palmeira (Autor) Outra; Miguel X Fernandes (Autor) Outra; Emilia Sousa (Autor) FFUP; Madalena Pinto (Autor) FFUP; Alberto Inga (Autor) Outra; Lucilia Saraiva (Autor) FFUP

Revista

Título: Biochemical Pharmacology

Vol. 85

Páginas: 1234-1245

ISSN: 0006-2952

Editora: Elsevier

Indexação

ISI Proceedings

ISI Web of Knowledge - 50 Citações

Scopus - 53 Citações

Classificação Científica

FOS: Ciências médicas e da saúde > Medicina básica

Outras Informações

ID Authenticus: P-005-1DF

DOI: 10.1016/j.bcp.2013.01.032

Abstract (EN): 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 I will pave the way for the structure-based design of a new class of p53-MDM2 inhibitors.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 12