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.
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|Titolo:||Discovery of a new small-molecule inhibitor of p53-MDM2 interaction using a yeast-based approach.|
|Autori:||M., Leão; C., Pereira; Bisio, Alessandra; Ciribilli, Yari; A. M., Paiva; N., Machado; A., Palmeira; M. X., Fernandes; E., Sousa; M., Pinto; Inga, Alberto; L., Saraiva|
|Titolo del periodico:||BIOCHEMICAL PHARMACOLOGY|
|Anno di pubblicazione:||2013|
|Codice identificativo Scopus:||2-s2.0-84875712215|
|Codice identificativo Pubmed:||23428467|
|Codice identificativo ISI:||WOS:000317320900004|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.bcp.2013.01.032|
|Appare nelle tipologie:||03.1 Articolo su rivista (Journal article)|