Medicinal Chemistry Strategies to Disrupt the p53-MDM2/MDMX Interaction

• Type: Another Publication in an International Scientific Journal
• Date: 2016

Authors

Lemos, A (Author) Other; Leao, M (Author) Other; Soares, J (Author) Other; Palmeira, A (Author) Other; Pinto, M (Author) Other; Lucilia Saraiva (Author) FFUP; Emilia Sousa (Author) FFUP

Journal

Title: Medicinal Research Reviews

Vol. 36

Pages: 789-844

ISSN: 0198-6325

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 56 Citations

Scopus - 0 Citations

Other information

Authenticus ID: P-00K-R2N

DOI: 10.1002/med.21393

Abstract (EN): The growth inhibitory activity of p53 tumor suppressor is tightly regulated by interaction with two negative regulatory proteins, murine double minute 2 (MDM2) and X (MDMX), which are overexpressed in about half of all human tumors. The elucidation of crystallographic structures of MDM2/MDMXcomplexes with p53 has been pivotal for the identification of several classes of inhibitors of the p53-MDM2/MDMX interaction. The present review provides in silico strategies and screening approaches used in drug discovery as well as an overview of the most relevant classes of small-molecule inhibitors of the p53-MDM2/MDMX interaction, their progress in pipeline, and highlights particularities of each class of inhibitors. Most of the progress made with high-throughput screening has led to the development of inhibitors belonging to the cis-imidazoline, piperidinone, and spiro-oxindole series. However, novel potent and selective classes of inhibitors of the p53-MDM2 interaction with promising antitumor activity are emerging. Even with the discovery of the 3D structure of complex p53-MDMX, only two small molecules were reported as selective p53-MDMX antagonists, WK298 and SJ-172550. Dual inhibition of the p53-MDM2/MDMX interaction has shown to be an alternative approach since it results in full activation of the p53-dependent pathway. The knowledge of structural requirements crucial to the development of small-molecule inhibitors of the p53-MDMs interactions has enabled the identification of novel antitumor agents with improved in vivo efficacy. (C) 2016 Wiley Periodicals, Inc.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 56