期刊
CHEMMEDCHEM
卷 11, 期 8, 页码 757-772出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201500487
关键词
cancer; conserved water; MDM2; MDMX; p53; protein-protein interactions
资金
- US National Institutes of Health (NIH) [1R01M097082]
- Department of Sciences, Technology, and Innovation-COLCIENCIAS (Colombia)
A recent therapeutic strategy in oncology is based on blocking the protein-protein interaction between the murine double minute (MDM) homologues MDM2/X and the tumor-suppressor protein p53. Inhibiting the binding between wild-type (WT) p53 and its negative regulators MDM2 and/or MDMX has become an important target in oncology to restore the antitumor activity of p53, the so-called guardian of our genome. Interestingly, based on the multiple disclosed compound classes and structural analysis of small-molecule-MDM2 adducts, the p53-MDM2 complex is perhaps the best studied and most targeted protein-protein interaction. Several classes of small molecules have been identified as potent, selective, and efficient inhibitors of the p53-MDM2/X interaction, and many co-crystal structures with the protein are available. Herein we review the properties as well as preclinical and clinical studies of these small molecules and peptides, categorized by scaffold type. A particular emphasis is made on crystallographic structures and the observed binding modes of these compounds, including conserved water molecules present.
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