3w69
From Proteopedia
Crystal structure of human mdm2 with a dihydroimidazothiazole inhibitor
Structural highlights
DiseaseMDM2_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. FunctionMDM2_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 PubMedWe have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53. Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors.,Miyazaki M, Naito H, Sugimoto Y, Yoshida K, Kawato H, Okayama T, Shimizu H, Miyazaki M, Kitagawa M, Seki T, Fukutake S, Shiose Y, Aonuma M, Soga T Bioorg Med Chem. 2013 Jul 15;21(14):4319-31. doi: 10.1016/j.bmc.2013.04.056. Epub, 2013 Apr 30. PMID:23685175[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations 1 reviews cite this structure No citations found See AlsoReferences
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Categories: Homo sapiens | Large Structures | Katakura S | Kawato H | Miyazaki M | Naito H | Okayama T | Shimizu H | Soga T | Sugimoto Y
