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

• Type: Article in International Scientific Journal
• Date: 2013

Authors

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

Journal

Title: Biochemical Pharmacology

Vol. 85

Pages: 1234-1245

ISSN: 0006-2952

Publisher: Elsevier

Indexing

ISI Proceedings

ISI Web of Knowledge - 50 Citations

Scopus - 53 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12