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

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.

Keywords

Xanthone derivatives Inhibitor of p53–MDM2 interaction Computational docking Yeast-based assays Antitumor activity . Faculdade de Ciências Exatas e da Engenharia

URI

http://hdl.handle.net/10400.13/5027

Citation

Leão, M., Pereira, C., Bisio, A., Ciribilli, Y., Paiva, A. M., Machado, N., ... & Saraiva, L. (2013). Discovery of a new small-molecule inhibitor of p53–MDM2 interaction using a yeast-based approach. Biochemical Pharmacology, 85(9), 1234-1245.