Portal de Periódicos da CAPES

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

2013; Elsevier BV; Volume: 85; Issue: 9 Linguagem: Inglês

10.1016/j.bcp.2013.01.032

1873-2968

Miguel Leão, Clara Pereira, Alessandra Bisio, Yari Ciribilli, Ana M. Oliveira Paiva, Neuza Machado, Andreia Palmeira, Miguel X. Fernandes, Emı́lia Sousa, Madalena Pinto, Alberto Inga, Lucı́lia Saraiva,

Ubiquitin and proteasome pathways

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.