4oq3
From Proteopedia
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| - | ==See Also== | ||
| - | *[[MDM2|MDM2]] | ||
== References == | == References == | ||
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Revision as of 08:29, 22 November 2017
Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction
Structural highlights
Disease[MDM2_HUMAN] Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding. Function[MDM2_HUMAN] E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] Publication Abstract from PubMedCapitalizing on crystal structure information obtained from a previous effort in the search for non peptide inhibitors of the p53-MDM2 interaction, we have discovered another new class of compounds able to disrupt this protein-protein interaction, an important target in oncology drug research. The new inhibitors, based on a tetra-substituted imidazole scaffold, have been optimized to low nanomolar potency in a biochemical assay following a structure-guided approach. An appropriate strategy has allowed us to translate the high biochemical potency in significant anti-proliferative activity on a p53-dependent MDM2 amplified cell line. Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction.,Vaupel A, Bold G, De Pover A, Stachyra-Valat T, Hergovich-Lisztwan J, Kallen J, Masuya K, Furet P Bioorg Med Chem Lett. 2014 May 1;24(9):2110-4. doi: 10.1016/j.bmcl.2014.03.039., Epub 2014 Mar 22. PMID:24704029[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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