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

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

Agostinho Lemos, Mariana Leão, Joana Soares, Andreia Palmeira, Madalena Pinto, Lucília Saraiva, Maria Emília Sousa

Med Res Rev. 2016 Sep;36(5):789-844.

PMID: 27302609

Abstract:

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/MDMX complexes 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP431979474	SJ-172550		431979-47-4	Price

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