Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 159, Issue -, Pages 1-9Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.09.044
Keywords
MDM2 inhibitors; MDM2-p53 interactions; Piperidinones; AMG-232; Cancer therapy
Categories
Funding
- National Natural Science Foundation of China [81773580]
- Department of Science and Technology of Guangdong Province, China [2017A050501032]
- Department of education of Guangdong Province, China [2016KZDXM031]
- Science and Technology Planning Program of Guangzhou City, China [201707010467]
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In tumor cells, p53 is always inactivated due to the mutation or deletion of TP53 gene or inhibited by the overexpressed MDM2. Small-molecule induced restoring of p53 function by blocking MDM2-p53 protein-protein interactions has been highly pursued as an attractive therapeutic strategy for cancer therapy. To date, a large number of small-molecule inhibitors have been identified based on the compact and well-defined MDM2-p53 interactions, of which SAR405838, MK-8242, DS-3032b, NVP-CGM097, RG7112, HDM201, RG7388, ALRN-6924 and AMG 232 are undergoing clinical assessment at different phases for cancer therapy. This review is focused on the discovery and development of piperidinone-based MDM2-p53 inhibitors for cancer therapy, including the identification of hit compounds, hit-to-lead optimizations, binding models of ligands in the active site of MDM2, metabolic studies, and preclinical data of advanced piperidinone-based MDM2-p53 inhibitors. Additionally, acquired resistance of MDM2 inhibitors and potential toxicity toward normal tissues are briefly discussed. (C) 2018 Elsevier Masson SAS. All rights reserved.
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